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Epigenetics and Human Disease
Abstract
Epigenetics is comprised of the stable and heritable (or potentially heritable) changes in gene expression that do not entail a change in DNA sequence. The role of epigenetics in the etiology of human disease is increasingly recognized with the most obvious evidence found for genes subject to genomic imprinting. Mutations and epimutations in imprinted genes can give rise to genetic and epigenetic phenotypes, respectively; uniparental disomy and imprinting defects represent epigenetic disease phenotypes. There are also genetic disorders that affect chromatin structure and remodeling. These disorders can affect chromatin in trans or in cis, as well as expression of both imprinted and nonimprinted genes. Data from Angelman and Beckwith-Wiedemann syndromes and other disorders indicate that a monogenic or oligogenic phenotype can be caused by a mixed epigenetic and genetic and mixed de novo and inherited (MEGDI) model. The MEGDI model may apply to some complex disease traits and could explain negative results in genome-wide genetic scans.
... DNA dizisinden bağımsız olarak gen ifadesinde meydana gelen kalıtsal değişiklikler ise "epigenetik değişiklikler" olarak adlandırılmaktadır. 1,2 Epigenetik mekanizmalar, çevresel etkenler ve henüz tanımlanmamış bazı faktörlerin de katkısıyla "epigenotip" adı verilen bir profil oluşturmaktadır. Genetik ve epigenetik mekanizmaların birlikte çalışması sonucu gen ekspresyonunda kalıcı değişiklikler meydana gelmektedir. ...
... Genotipin bu genetik ve epigenetik üzerindeki yansıması ise fenotipi oluşturmaktadır. 1 Epigenetik mekanizmaların işleyişinde ortaya çıkabilecek bir bozukluk genlerin ekspresyonlarında artış veya baskılanmaya neden olur ve epigenetik hastalıklara yol açabilir. 2 Bu hastalıklara; Angelman sendromu, otizm spektrum bozukluk-ları, Beckwith-Wiedemann Sendromu, Fragile X sendromu, Prader-Willi sendromu, metabolik sendrom, Rett sendromu ve Russell-Silver sendromu örnek olarak verilebilir. ...
... Mounting evidence confirms that the epigenetic mechanisms controlling the gene expression system play a vital role in modulating cellular functions in response to environmental changes [4][5][6][7][8]. These epigenetic mechanisms lie at the center of regulating stress responses, metabolic pathways, and diseases (e.g., neurological disorders, chronic inflammation, microbial infections, and cancers) [9][10][11]. The posttranslational modifications, molecular interactions, and noncoding RNAs comprise major epigenetic mechanisms that regulate the outcomes of gene transcription [12][13][14][15]. ...
... For instance, deregulated dynamics of KATs or KDACs on the androgen receptor (AR) target gene promoters escalate anti-androgen resistance, which leads to the growth and metastasis of prostate cancer (PCa) cells [33][34][35]. These data implicate the translational significance of coactivators, which have naturally become the target for a generation of new medicines [9,36]. Gene manipulation strategies may not be widely useful, for at least two reasons: first, coactivators are multidomain proteins that mediate several functions, and second, gene editing can generate unintended secondary mutations and off-target effects [37]. ...
The molecular interplay between nucleosomal packaging and the chromatin landscape regulates the transcriptional programming and biological outcomes of downstream genes. An array of epigenetic modifications plays a pivotal role in shaping the chromatin architecture, which controls DNA access to the transcriptional machinery. Acetylation of the amino acid lysine is a widespread epigenetic modification that serves as a marker for gene activation, which intertwines the maintenance of cellular homeostasis and the regulation of signaling during stress. The biochemical horizon of acetylation ranges from orchestrating the stability and cellular localization of proteins that engage in the cell cycle to DNA repair and metabolism. Furthermore, lysine acetyltransferases (KATs) modulate the functions of transcription factors that govern cellular response to microbial infections, genotoxic stress, and inflammation. Due to their central role in many biological processes, mutations in KATs cause developmental and intellectual challenges and metabolic disorders. Despite the availability of tools for detecting acetylation, the mechanistic knowledge of acetylation-mediated cellular processes remains limited. This review aims to integrate molecular and structural bases of KAT functions, which would help design highly selective tools for understanding the biology of KATs toward developing new disease treatments.
... Recent advances have highlighted the role that alterations in the epigenetic machinery play in human disease [33][34][35] . In the field of precision medicine, epigenetic mutations are currently examined mainly for their potential role in early detection and drug response prediction [36][37][38] . ...
Epigenetic modifications are dynamic mechanisms involved in the regulation of gene expression. Unlike the DNA sequence, epigenetic patterns vary not only between individuals, but also between different cell types within an individual. Environmental factors, somatic mutations and ageing contribute to epigenetic changes that may constitute early hallmarks or causal factors of disease. Epigenetic modifications are reversible and thus promising therapeutic targets for precision medicine. However, mapping efforts to determine an individual’s cell-type-specific epigenome are constrained by experimental costs and tissue accessibility. To address these challenges, we developed eDICE, an attention-based deep learning model that is trained to impute missing epigenomic tracks by conditioning on observed tracks. Using a recently published set of epigenomes from four individual donors, we show that transfer learning across individuals allows eDICE to successfully predict individual-specific epigenetic variation even in tissues that are unmapped in a given donor. These results highlight the potential of machine learning-based imputation methods to advance personalized epigenomics.
... Hücre siklusu, DNA tamir mekanizması, hücrelerarası sinyalleşme, transkripsiyon ve apoptoz gibi süreçlerde önemli rol oynayan genler, çoğu tümör türlerinde anormal seviyede hipermetile olarak sessizleşmektedir. Bunun sonucunda tümör hücreleri büyüme avantaj kazanarak genomik kararsızlıkta artış ortaya çıkmaktadır [1,17,18]. ...
... Rett syndrome is caused by mutations in MECP2 gene, which encodes for the methylated DNA binding protein MeCP2 [35], causing either the activation or the inhibition of gene transcription, depending on the genomic context [36]. Interestingly, beside Rett syndrome, also Fragile X syndrome, Angelman syndrome, and Beckwith-Wiedemann syndrome, are all caused by epigenetic dysregulation, and each one shares a phenotypic overlap with ASD [37,38]. ...
The wide spectrum of unique needs and strengths of Autism Spectrum Disorders (ASD) is a challenge for the worldwide healthcare system. With the plethora of information from research, a common thread is required to conceptualize an exhaustive pathogenetic paradigm. The epidemiological and clinical findings in ASD cannot be explained by the traditional linear genetic model, hence the need to move towards a more fluid conception, integrating genetics, environment, and epigenetics as a whole. The embryo-fetal period and the first two years of life (the so-called 'First 1000 Days') are the crucial time window for neurodevelopment. In particular, the interplay and the vicious loop between immune activation, gut dysbiosis, and mitochondrial impairment/oxidative stress significantly affects neurodevelopment during pregnancy and undermines the health of ASD people throughout life. Consequently, the most effective intervention in ASD is expected by primary prevention aimed at pregnancy and at early control of the main effector molecular pathways. We will reason here on a comprehensive and exhaustive pathogenetic paradigm in ASD, viewed not just as a theoretical issue, but as a tool to provide suggestions for effective preventive strategies and personalized, dynamic (from womb to adulthood), systemic, and interdisciplinary healthcare approach
... Epigenetic modifications of the genome contain multiple types, such as covalent modifications on DNA and histones, chromatin accessibility and compaction, as well as the higher order conformation of chromosome domains ( Figure 2). These modifications form intricate regulatory networks that can influence the chromatin structure and gene expression, which may contribute to the initiation and/or progression of different diseases [24][25][26][27]. Single-cell epigenome profiling is useful for revealing how epigenetics influences gene expression, cell lineage and cell fate at single-cell resolution, as well as elucidating the identity, function and phenotypes of cells [28][29][30]. ...
Multi-omics allows the systematic understanding of the information flow across different omics layers, while single omics can mainly reflect one aspect of the biological system. The advancement of bulk and single-cell sequencing technologies and related computational methods for multi-omics largely facilitated the development of system biology and precision medicine. Single-cell approaches have the advantage of dissecting cellular dynamics and heterogeneity, whereas traditional bulk technologies are limited to individual/population-level investigation. In this review, we first summarize the technologies for producing bulk and single-cell multi-omics data. Then, we survey the computational approaches for integrative analysis of bulk and single-cell multimodal data, respectively. Moreover, the databases and data storage for multi-omics, as well as the tools for visualizing multimodal data are summarized. We also outline the integration between bulk and single-cell data, and discuss the applications of multi-omics in precision medicine. Finally, we present the challenges and perspectives for multi-omics development.
... Rett syndrome is caused by mutations in MECP2 gene, which encodes for the methylated DNA binding protein MeCP2 [35], causing either the activation or the inhibition of gene transcription, depending on the genomic context [36]. Interestingly, beside Rett syndrome, also Fragile X syndrome, Angelman syndrome, and Beckwith-Wiedemann syndrome, are all caused by epigenetic dysregulation, and each one shares a phenotypic overlap with ASD [37,38]. ...
The wide spectrum of unique needs and strengths of Autism Spectrum Disorders (ASD) is a challenge for the worldwide healthcare system. With the plethora of information from research, a common thread is required to conceptualize an exhaustive pathogenetic paradigm. The epidemiological and clinical findings in ASD cannot be explained by the traditional linear genetic model, hence the need to move towards a more fluid conception, integrating genetics, environment, and epigenetics as a whole. The embryo-fetal period and the first two years of life (the so-called ‘First 1000 Days’) are the crucial time window for neurodevelopment. In particular, the interplay and the vicious loop between immune activation, gut dysbiosis, and mitochondrial impairment/oxidative stress significantly affects neurodevelopment during pregnancy and undermines the health of ASD people throughout life. Consequently, the most effective intervention in ASD is expected by primary prevention aimed at pregnancy and at early control of the main effector molecular pathways. We will reason here on a comprehensive and exhaustive pathogenetic paradigm in ASD, viewed not just as a theoretical issue, but as a tool to provide suggestions for effective preventive strategies and personalized, dynamic (from womb to adulthood), systemic, and interdisciplinary healthcare approach.
... Also, epigenetic alterations feature inconsiderate up and downregulation of various signaling pathways, which may lead to the pathogenesis of cancer [9,10]. Thus, epigenetics play a decisive role in mammalian development and stable epigenetic inheritance, necessary for maintaining tissue and cells specific function [11,12]. ...
The non-enzymatic glycosylation or non-enzymatic covalent modifications (NECMs) or glycation of cellular proteins result in the generation and accumulation of advanced glycation end products (AGEs) that are associated with the epigenetics of cancer. Epigenetic modifications are inheritable changes without alterations in the sequences of DNA. Glycation-mediated epigenetic mechanisms change the accessibility of transcriptional factors to DNA via rearrangement or modification in the chromatin structure and collaborate with gene regulation in the pathogenesis of cancer. Epigenetic mechanisms play a critical role in sustaining the tissue-specific gene expression. Distraction from normal epigenetic mechanism results in alteration of gene function, initiation and progression of cancer, and cellular malignant transformation. Epigenetic modifications on DNA and histones control enzymatic expressions of corresponding metabolic pathways, which in turn influence epigenetic regulation. Glycation of histones due to persistent hyperglycemia results in histone-histone and histone-DNA cross-linking in chromatin by compromising the electrostatic interactions, that affect the dynamic architecture of chromatin. Histone proteins are highly prone to glycation due to their basic nature and long half-lives, but the exact role of histone glycation in the epigenetics of cancer is still in the veil. However, recent studies have suggested the role of histone glycation mediated epigenetic modifications that affect cellular functioning by altering the gene expressions of related metabolic pathways. Moreover, dicarbonyls-induced NECMs of histones perturb the architecture of chromatin and transcription of genes via multiple mechanisms. Contrary to the genetic causes of cancer, a possible reversal of glycation-mediated epigenetic modifications might open a new realm for therapeutic interventions. In this review, we have portrayed a mechanistic link between histone glycation and cancer epigenetics.
... These often affect synaptic genes, and associated CNVs tend to occur in genome regions that are prone to recurrent mutations (76) and are implicated in schizophrenia (77,78). The second random feature implicated in schizophrenia is epimutations, particularly changes in DNA methylation (79). They may undergo such changes randomly or in response to external exposures and be passed on through succeeding mitotic cycles (9,16). ...
The search for what causes schizophrenia has been onerous. This research has included extensive assessment of a variety of genetic and environmental factors using ever emerging high-resolution technologies and traditional understanding of the biology of the brain. These efforts have identified a large number of schizophrenia-associated genes, some of which are altered by mutational and epi-mutational mechanisms in a threshold liability model of schizophrenia development. The results, however, have limited predictability and the actual cause of the disease remains unknown. This current state asks for conceptualizing the problem differently in light of novel insights into the nature of mutations, the biology of the brain and the fine precision and resolution of emerging technologies. There is mounting evidence that mutations acquired during postzygotic development are more common than germline mutations. Also, the postzygotic somatic mutations including epimutations (PZMs), which often lead to somatic mosaicism, are relatively common in the mammalian brain in comparison to most other tissues and PZMs are more common in patients with neurodevelopmental mental disorders, including schizophrenia. Further, previously inaccessible, detection of PZMs is becoming feasible with the advent of novel technologies that include single-cell genomics and epigenomics and the use of exquisite experimental designs including use of monozygotic twins discordant for the disease. These developments allow us to propose a working hypothesis and expand the threshold liability model of schizophrenia that already encompasses familial genetic, epigenetic and environmental factors to include somatic de novo PZMs. Further, we offer a test for this expanded model using currently available genome sequences and methylome data on monozygotic twins discordant for schizophrenia (MZD) and their parents. The results of this analysis argue that PZMs play a significant role in the development of schizophrenia and explain extensive heterogeneity seen across patients. It also offers the potential to convincingly link PZMs to both nervous system health and disease, an area that has remained challenging to study and relatively under explored.
... Epigenetics can modify gene expression, including completely silencing genes and mobile genetic elements, and also be responsible for altering genome structures (e.g., Bernstein and Allis 2005;Heard and Martienssen 2014). The effects of these epigenetic processes range from cell differentiation to genomic imprinting and, in cases where they malfunction, disease (e.g., Jiang et al. 2004;Gluckman et al. 2009;Handel et al. 2010). Epigenetics also plays a role in shaping genome architectures through DNA rearrangement/ elimination and polyploidization in diverse lineages of eukaryotes (e.g., Liu and Wendel 2003;Maurer-Alcal a and Katz 2015). ...
Epigenetic processes in eukaryotes play important roles through regulation of gene expression, chromatin structure and genome rearrangements. Mechanisms such as chromatin modification (e.g. DNA methylation, histone modification) and non-protein-coding RNAs (npc-RNAs) have been well studied in animals and plants. With the exception of a few model organisms (e.g. Saccharomyces, Plasmodium), much less is known about epigenetic toolkits across the remainder of the eukaryotic tree of life. Even with limited data, previous work suggested the existence of an ancient epigenetic toolkit in the last eukaryotic common ancestor (LECA). We use PhyloToL, our taxon-rich phylogenomic pipeline, to detect homologs of epigenetic genes and evaluate their macroevolutionary patterns among eukaryotes. In addition to data from GenBank, we increase taxon sampling from understudied clades of SAR (Stramenopila, Alveolata and Rhizaria) and Amoebozoa by adding new single-cell transcriptomes from ciliates, foraminifera and testate amoebae. We focus on 118 gene families, 94 involved in chromatin modification and 24 involved in npc-RNA processes based on the epigenetics literature. Our results indicate: 1) the presence of a large number of epigenetic gene families in LECA; 2) differential conservation among major eukaryotic clades, with a notable paucity of genes within Excavata; and 3) punctate distribution of epigenetic gene families between species consistent with rapid evolution leading to gene loss. Together these data demonstrate the power of taxon-rich phylogenomic studies for illuminating evolutionary patterns at scales of > 1 billion years of evolution and suggest that macroevolutionary phenomena, such as genome conflict, have shaped the evolution of the eukaryotic epigenetic toolkit.
... It involves the addition of acetyl groups on the histone N-terminal tail by histone acetyl transferases (HAT). There are two types of HAT: Type A contains a bromodomain, that is found in the nucleus and acetylates chromatin and nucleosomal histones, for example Gcn5/PCAF and CBP/p300; Type B is found in the cytoplasm and acetylates newly transcribed histones [108]. Acetylation results in a relaxed chromatin structure that allows for transcriptional activation [109]. ...
The formation of adipocytes during embryogenesis has been largely understudied. However, preadipocytes appear to originate from multipotent mesenchymal stromal/stem cells which migrate from the mesoderm to their anatomical localization. Most studies on adipocyte formation (adipogenesis) have used preadipocytes derived from adult stem/stromal cells. Adipogenesis consists of two phases, namely commitment and terminal differentiation. This review discusses the role of signalling pathways, epigenetic modifiers, and transcription factors in preadipocyte commitment and differentiation into mature adipocytes, as well as limitations in our understanding of these processes. To date, a limited number of transcription factors, genes and signalling pathways have been described to regulate preadipocyte commitment. One reason could be that most studies on adipogenesis have used preadipocytes already committed to the adipogenic lineage, which are therefore not suitable for studying preadipocyte commitment. Conversely, over a dozen molecular players including transcription factors, genes, signalling pathways, epigenetic regulators, and microRNAs have been described to be involved in the differentiation of preadipocytes to adipocytes; however, only peroxisome proliferator-activated receptor gamma has proven to be clinically relevant. A detailed understanding of how the molecular players underpinning adipogenesis relate to adipose tissue function could provide new therapeutic approaches for addressing obesity without compromising adipose tissue function.
... In the early 1940 s, Conrad Waddington defined the term 'epigenetics' as the branch of biology that studies the causal interactions between genes and their products, which lead to a certain phenotype. Currently, epigenetics can be defined as stable and inheritable changes in gene expression which are not produced by changes in the DNA sequence [1][2][3]. The most studied epigenetic modifications are DNA methylation and posttranslational histone modifications, which participate in the regulation of gene expression in presence of a complex interaction of activator or inhibitor factors such as noncoding RNAs (ncRNAs) of different lengthslinear RNAs, long ncRNAs (lncRNAs) of~200 bp or microRNAs (miRs) of~25 bp, and circular RNAs (circRNAs). ...
Introduction
Fatty liver disease, defined by the presence of liver fat infiltration, is part of a cluster of disorders that occur in the context of metabolic syndrome. Epigenetic factors – defined as stable and heritable changes in gene expression without changes in the DNA sequence – may not only play an important role in the disease development in adulthood, but they may start exerting their influence in the prenatal stage.
Areas covered
By using systems biology approaches, we review the main epigenetic modifications and highlight their likely roles in the pathogenesis of nonalcoholic fatty liver disease.
Expert opinion
Knowledge of the mechanisms by which epigenetic modifications participate in complex disorders would not only help scientists find novel therapeutic strategies but could also aid in implementing preventive care measures at gestation.
... It is increasingly clear that epigenetics, defined as modifications in gene expression that are controlled by heritable but potentially reversible changes in DNA methylation or chromatin structure without altering the DNA sequence, are important in the pathogenesis of IBD. [96][97][98] Further, epigenetic markers have emerged as a powerful predictor of disease course and the need for treatment escalation in IBD. 99 Importantly, epigenetic modifications can be both tissue-and cell-type specific, and thus traditional epigenetic analysis using bulk measurements of heterogenous cell populations may easily miss functionally critical epigenetic marks. ...
The intestinal mucosa represents a unique environment where the coordinated function of diverse epithelial, mesenchymal, and immune cells maintains a physiologically balanced environment in the presence of gut microbiota. The intestinal mucosa plays a central role in the pathogenesis of inflammatory bowel disease (IBD), yet the molecular and cellular composition of this diverse environment is poorly understood. However, the recent advent of multimodal single-cell technologies, including single-cell RNA sequencing (scRNA-seq), now provides an opportunity to accurately map the tissue architecture, characterize rare cell types that were previously overlooked, and define function at a single-cell level. In this review, we summarize key advances in single-cell technology and provide an overview of important aspects of computational analysis. We describe emerging data in the field of IBD and discuss how the characterization of novel intestinal mucosa cell populations is reshaping our understanding of this complex disease. We conclude by considering the potential clinical applications, including the definition of novel drug targets and the opportunity for personalization of care in this exciting new era of precision medicine.
... Chemical modification patterns on histone tails and DNA collectively constitute the epigenome that dictates unique gene expression patterns and resulting phenotypes in each distinct cell type [1][2][3]. The alterations of the epigenome due to the dysregulation of epigenome pathways and mutations of epigenome regulators contributes to pathogenesis of various human diseases including many developmental diseases and cancers [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Several epigenetic regulatory mechanisms including DNA methylations, histone tail posttranslational modifications (PTMs), ATP-dependent chromatin remodeling and non-coding RNAs have been shown to play key roles in governing gene activities [6,7,15,[20][21][22][23][24][25][26][27][28][29]. ...
The epigenome defines the unique gene expression patterns and resulting cellular behaviors in different cell types. Epigenome dysregulation has been directly linked to various human diseases. Epigenome editing enabling genome locus-specific targeting of epigenome modifiers to directly alter specific local epigenome modifications offers a revolutionary tool for mechanistic studies in epigenome regulation as well as the development of novel epigenome therapies. Inducible and reversible epigenome editing provides unique temporal control critical for understanding the dynamics and kinetics of epigenome regulation. This review summarizes the progress in the development of spatiotemporal-specific tools using small molecules or light as inducers to achieve the conditional control of epigenome editing and their applications in epigenetic research.
... They control genomic stability, development, X chromosome inactivation, etc. [290]. Disruption of the epigenome, also known as induction of epimutations, [119] has an essential role in disease development [71,103,134]. Therefore, the multifaceted interaction involving the genetic system and epigenetic marks embossed in the genetic system by exogenous or endogenous factors plays a huge role in disease susceptibility [131]. ...
... [10][11][12] Epigenetic modifications comprise multiple biochemical mechanisms, such as chromatin modifications on histones and DNA methylation among others, 13 and are crucial for the development and differentiation of various cell types. 14,15 Histone acetylation induced by histone acetyl transferases is associated with gene transcription, whereas histone deacetylases (HDACs) remove acetyl groups from hyperacetylated histones, suppressing gene transcription. Eighteen HDACs have been identified and are classified in 4 groups. ...
Background:
A defective epithelial barrier is found in patients with allergic rhinitis (AR) and asthma; however, the underlying mechanisms remain poorly understood. Histone deacetylase (HDAC) activity has been identified as a crucial driver of allergic inflammation and tight junction dysfunction.
Objective:
We investigated whether HDAC activity has been altered in patients with AR and in a mouse model of house dust mite (HDM)-induced allergic asthma and whether it contributed to epithelial barrier dysfunction.
Methods:
Primary nasal epithelial cells of control subjects and patients with AR were cultured at the air-liquid interface to study transepithelial electrical resistance and paracellular flux of fluorescein isothiocyanate-dextran (4 kDa) together with mRNA expression and immunofluorescence staining of tight junctions. Air-liquid interface cultures were stimulated with different concentrations of JNJ-26481585, a broad-spectrum HDAC inhibitor. In vivo the effect of JNJ-26481585 on mucosal permeability and tight junction function was evaluated in a mouse model of HDM-induced allergic airway inflammation.
Results:
General HDAC activity was greater in nasal epithelial cells of patients with AR and correlated inversely with epithelial integrity. Treatment of nasal epithelial cells with JNJ-26481585 restored epithelial integrity by promoting tight junction expression and protein reorganization. HDM-sensitized mice were treated with JNJ-26481585 to demonstrate the in vivo role of HDACs. Treated mice did not have allergic airway inflammation and had no bronchial hyperreactivity. Moreover, JNJ-26481585 treatment restored nasal mucosal function by promoting tight junction expression.
Conclusion:
Our findings identify increased HDAC activity as a potential tissue-injury mechanism responsible for dysregulated epithelial cell repair, leading to defective epithelial barriers in AR. Blocking HDAC activity is a promising novel target for therapeutic intervention in patients with airway diseases.
A significant increase in the prevalence of autism spectrum disorders (ASD), both worldwide and in our country, dictates the need to search for modern and effective methods of prevention, diagnosis and medical care for such patients. At the same time, the results of numerous biomedical research in the field of autism are not reflected in practical healthcare. Aims of this work — substantiation of new approaches to the organization of medical care for people with ASD. The results of promising areas of autism research in the field of genetics, epigenetics, metabolomics, microbiome and multimorbidity, which marked a paradigm shift in the understanding of autism spectrum disorders, and requiring implementation in practice, are analyzed. Based on the concept of 7-p pediatrics (programming child development and health, preventive, predictive, personalized, participatory, multiprofessional, progressive), the necessity and possibility of implementing the results of scientific research into real clinical practice of managing children with autism are substantiated. The results of fundamental scientific research in the field of ASD, revealing their complex and multifaceted nature, allow us to talk about a paradigm shift in understanding this disorder Based on a new concept of medical care — 7P-pediatrics — the results of scientific research can be translated into real clinical practice, including diagnostic, therapeutic, preventive and rehabilitative effects on autism, as well ase programming of the optimal trajectory of the cognitive-behavioral phenotype of children with neurodevelopmental features, including ASD.
Bioinformatics can speed up the identification of therapeutic targets, screening drug candidates, and refinement of those candidates. It can also make it easier to characterise side effects and anticipate drug resistance. Data from transcriptomic, proteomic, transcriptomic architecture, ribosome profiling, epigenetic, cistromic, and genomic sources, among other high-throughput data, have all contributed significantly to the development of mechanism-based drugs and pharmacological repurposing. Large-scale databases of tiny chemicals’ structures and metabolites, along with the building up of RNA and protein structures, predictions of protein structure and homology mapping, provided the ground for much accurate docking of protein and compound investigations and much insightful virtual refining. The outlined conceptual framework underpins the high-throughput data storage, summarises the value and mining potential for these data for drugs, and points out some underlying restrictions inside the data and the programs used to mine them, indicating novel approaches to improve examination of these different information formats, highlighting popular libraries, and software that are pertinent to drugs.KeywordsBioinformaticsTranscriptomicsProteomicsEpigeneticsCirtromicsRibosome profilingPharmacological repurposing
Among the skin disorders reflecting mosaicism, two major morphological categories are nonsegmental and segmental mosaicism. On the other hand, two major genetic categories are genomic mosaics and epigenetic mosaics. In genomic mosaicism we can discriminate lethal from nonlethal mutations. Lethal mutations can only survive in a mosaic state. By contrast, nonlethal mutations, when transmitted to the next generation, cause a diffuse, nonmosaic involvement, or they give rise to disseminated mosaicism as noted, for example, in hereditary traits characterized by multiple benign skin tumors. A simple segmental manifestation reflects a postzygotic mutation occurring in an otherwise healthy embryo, whereas a superimposed mosaic manifestation is overlaid on a diffuse, nonsegmental involvement and reflects loss of the corresponding wild-type allele occurring in a heterozygous embryo. In common polygenic skin disorders such as psoriasis, a pronounced, superimposed segmental manifestation may originate from early loss of heterozygosity or from a postzygotic new mutation occurring at an additional predisposing gene locus. In autosomal recessive traits, heterozygous individuals are usually healthy. Rarely, however, the disorder becomes manifest in mosaic form when the corresponding wild-type allele is lost at an early developmental stage, giving rise to a homozygous or compound heterozygous patch. Twin spots are paired patches that differ genetically from each other and from the surrounding background tissue. In human skin, possible examples are cutis tricolor and paired nevus flammeus and nevus anemicus. In epidermolysis bullosa and other genodermatoses, revertant mosaicism may result from a postzygotic back mutation, giving rise to patches of healthy skin. Epigenetic mosaicism of autosomes has been studied in mice and dogs and may also occur in humans. Epigenetic mosaicism of X chromosomes results in a linear or otherwise segmental pattern in various X-linked skin disorders. In some of these traits such as incontinentia pigmenti or focal dermal hypoplasia, X inactivation accounts for survival of female embryos, whereas male embryos carrying the mutation usually die in utero. By way of exception, however, male embryos with a 46,XY karyotype may survive because they carry a postzygotic new mutation giving rise to genomic mosaicism, or because they have a 47,XXY karyotype resulting in functional X-chromosome mosaicism. It should be borne in mind that not all of the X-linked human genes are inactivated. For example, the gene of X-linked recessive ichthyosis escapes inactivation, which is why female gene carries display a completely normal phenotype.
With over 200 types of cancer diagnosed to date, researchers the world over have been forced to rapidly update their understanding of the biology of cancer. In fact, only the study of the basic cellular processes, and how these are altered in cancer cells, can ultimately provide a background for rational therapies. Bringing together the state-of-the-art contributions of international experts, Systems Biology of Cancer proposes an ultimate research goal for the whole scientific community: exploiting systems biology to generate in-depth knowledge based on blueprints that are unique to each type of cancer. Readers are provided with a realistic view of what is known and what is yet to be uncovered on the aberrations in the fundamental biological processes, deregulation of major signaling networks, alterations in major cancers and the strategies for using the scientific knowledge for effective diagnosis, prognosis and drug discovery to improve public health.
With over 200 types of cancer diagnosed to date, researchers the world over have been forced to rapidly update their understanding of the biology of cancer. In fact, only the study of the basic cellular processes, and how these are altered in cancer cells, can ultimately provide a background for rational therapies. Bringing together the state-of-the-art contributions of international experts, Systems Biology of Cancer proposes an ultimate research goal for the whole scientific community: exploiting systems biology to generate in-depth knowledge based on blueprints that are unique to each type of cancer. Readers are provided with a realistic view of what is known and what is yet to be uncovered on the aberrations in the fundamental biological processes, deregulation of major signaling networks, alterations in major cancers and the strategies for using the scientific knowledge for effective diagnosis, prognosis and drug discovery to improve public health.
With over 200 types of cancer diagnosed to date, researchers the world over have been forced to rapidly update their understanding of the biology of cancer. In fact, only the study of the basic cellular processes, and how these are altered in cancer cells, can ultimately provide a background for rational therapies. Bringing together the state-of-the-art contributions of international experts, Systems Biology of Cancer proposes an ultimate research goal for the whole scientific community: exploiting systems biology to generate in-depth knowledge based on blueprints that are unique to each type of cancer. Readers are provided with a realistic view of what is known and what is yet to be uncovered on the aberrations in the fundamental biological processes, deregulation of major signaling networks, alterations in major cancers and the strategies for using the scientific knowledge for effective diagnosis, prognosis and drug discovery to improve public health.
With over 200 types of cancer diagnosed to date, researchers the world over have been forced to rapidly update their understanding of the biology of cancer. In fact, only the study of the basic cellular processes, and how these are altered in cancer cells, can ultimately provide a background for rational therapies. Bringing together the state-of-the-art contributions of international experts, Systems Biology of Cancer proposes an ultimate research goal for the whole scientific community: exploiting systems biology to generate in-depth knowledge based on blueprints that are unique to each type of cancer. Readers are provided with a realistic view of what is known and what is yet to be uncovered on the aberrations in the fundamental biological processes, deregulation of major signaling networks, alterations in major cancers and the strategies for using the scientific knowledge for effective diagnosis, prognosis and drug discovery to improve public health.
With over 200 types of cancer diagnosed to date, researchers the world over have been forced to rapidly update their understanding of the biology of cancer. In fact, only the study of the basic cellular processes, and how these are altered in cancer cells, can ultimately provide a background for rational therapies. Bringing together the state-of-the-art contributions of international experts, Systems Biology of Cancer proposes an ultimate research goal for the whole scientific community: exploiting systems biology to generate in-depth knowledge based on blueprints that are unique to each type of cancer. Readers are provided with a realistic view of what is known and what is yet to be uncovered on the aberrations in the fundamental biological processes, deregulation of major signaling networks, alterations in major cancers and the strategies for using the scientific knowledge for effective diagnosis, prognosis and drug discovery to improve public health.
With over 200 types of cancer diagnosed to date, researchers the world over have been forced to rapidly update their understanding of the biology of cancer. In fact, only the study of the basic cellular processes, and how these are altered in cancer cells, can ultimately provide a background for rational therapies. Bringing together the state-of-the-art contributions of international experts, Systems Biology of Cancer proposes an ultimate research goal for the whole scientific community: exploiting systems biology to generate in-depth knowledge based on blueprints that are unique to each type of cancer. Readers are provided with a realistic view of what is known and what is yet to be uncovered on the aberrations in the fundamental biological processes, deregulation of major signaling networks, alterations in major cancers and the strategies for using the scientific knowledge for effective diagnosis, prognosis and drug discovery to improve public health.
With over 200 types of cancer diagnosed to date, researchers the world over have been forced to rapidly update their understanding of the biology of cancer. In fact, only the study of the basic cellular processes, and how these are altered in cancer cells, can ultimately provide a background for rational therapies. Bringing together the state-of-the-art contributions of international experts, Systems Biology of Cancer proposes an ultimate research goal for the whole scientific community: exploiting systems biology to generate in-depth knowledge based on blueprints that are unique to each type of cancer. Readers are provided with a realistic view of what is known and what is yet to be uncovered on the aberrations in the fundamental biological processes, deregulation of major signaling networks, alterations in major cancers and the strategies for using the scientific knowledge for effective diagnosis, prognosis and drug discovery to improve public health.
With over 200 types of cancer diagnosed to date, researchers the world over have been forced to rapidly update their understanding of the biology of cancer. In fact, only the study of the basic cellular processes, and how these are altered in cancer cells, can ultimately provide a background for rational therapies. Bringing together the state-of-the-art contributions of international experts, Systems Biology of Cancer proposes an ultimate research goal for the whole scientific community: exploiting systems biology to generate in-depth knowledge based on blueprints that are unique to each type of cancer. Readers are provided with a realistic view of what is known and what is yet to be uncovered on the aberrations in the fundamental biological processes, deregulation of major signaling networks, alterations in major cancers and the strategies for using the scientific knowledge for effective diagnosis, prognosis and drug discovery to improve public health.
With over 200 types of cancer diagnosed to date, researchers the world over have been forced to rapidly update their understanding of the biology of cancer. In fact, only the study of the basic cellular processes, and how these are altered in cancer cells, can ultimately provide a background for rational therapies. Bringing together the state-of-the-art contributions of international experts, Systems Biology of Cancer proposes an ultimate research goal for the whole scientific community: exploiting systems biology to generate in-depth knowledge based on blueprints that are unique to each type of cancer. Readers are provided with a realistic view of what is known and what is yet to be uncovered on the aberrations in the fundamental biological processes, deregulation of major signaling networks, alterations in major cancers and the strategies for using the scientific knowledge for effective diagnosis, prognosis and drug discovery to improve public health.
With over 200 types of cancer diagnosed to date, researchers the world over have been forced to rapidly update their understanding of the biology of cancer. In fact, only the study of the basic cellular processes, and how these are altered in cancer cells, can ultimately provide a background for rational therapies. Bringing together the state-of-the-art contributions of international experts, Systems Biology of Cancer proposes an ultimate research goal for the whole scientific community: exploiting systems biology to generate in-depth knowledge based on blueprints that are unique to each type of cancer. Readers are provided with a realistic view of what is known and what is yet to be uncovered on the aberrations in the fundamental biological processes, deregulation of major signaling networks, alterations in major cancers and the strategies for using the scientific knowledge for effective diagnosis, prognosis and drug discovery to improve public health.
With over 200 types of cancer diagnosed to date, researchers the world over have been forced to rapidly update their understanding of the biology of cancer. In fact, only the study of the basic cellular processes, and how these are altered in cancer cells, can ultimately provide a background for rational therapies. Bringing together the state-of-the-art contributions of international experts, Systems Biology of Cancer proposes an ultimate research goal for the whole scientific community: exploiting systems biology to generate in-depth knowledge based on blueprints that are unique to each type of cancer. Readers are provided with a realistic view of what is known and what is yet to be uncovered on the aberrations in the fundamental biological processes, deregulation of major signaling networks, alterations in major cancers and the strategies for using the scientific knowledge for effective diagnosis, prognosis and drug discovery to improve public health.
With over 200 types of cancer diagnosed to date, researchers the world over have been forced to rapidly update their understanding of the biology of cancer. In fact, only the study of the basic cellular processes, and how these are altered in cancer cells, can ultimately provide a background for rational therapies. Bringing together the state-of-the-art contributions of international experts, Systems Biology of Cancer proposes an ultimate research goal for the whole scientific community: exploiting systems biology to generate in-depth knowledge based on blueprints that are unique to each type of cancer. Readers are provided with a realistic view of what is known and what is yet to be uncovered on the aberrations in the fundamental biological processes, deregulation of major signaling networks, alterations in major cancers and the strategies for using the scientific knowledge for effective diagnosis, prognosis and drug discovery to improve public health.
With over 200 types of cancer diagnosed to date, researchers the world over have been forced to rapidly update their understanding of the biology of cancer. In fact, only the study of the basic cellular processes, and how these are altered in cancer cells, can ultimately provide a background for rational therapies. Bringing together the state-of-the-art contributions of international experts, Systems Biology of Cancer proposes an ultimate research goal for the whole scientific community: exploiting systems biology to generate in-depth knowledge based on blueprints that are unique to each type of cancer. Readers are provided with a realistic view of what is known and what is yet to be uncovered on the aberrations in the fundamental biological processes, deregulation of major signaling networks, alterations in major cancers and the strategies for using the scientific knowledge for effective diagnosis, prognosis and drug discovery to improve public health.
With over 200 types of cancer diagnosed to date, researchers the world over have been forced to rapidly update their understanding of the biology of cancer. In fact, only the study of the basic cellular processes, and how these are altered in cancer cells, can ultimately provide a background for rational therapies. Bringing together the state-of-the-art contributions of international experts, Systems Biology of Cancer proposes an ultimate research goal for the whole scientific community: exploiting systems biology to generate in-depth knowledge based on blueprints that are unique to each type of cancer. Readers are provided with a realistic view of what is known and what is yet to be uncovered on the aberrations in the fundamental biological processes, deregulation of major signaling networks, alterations in major cancers and the strategies for using the scientific knowledge for effective diagnosis, prognosis and drug discovery to improve public health.
With over 200 types of cancer diagnosed to date, researchers the world over have been forced to rapidly update their understanding of the biology of cancer. In fact, only the study of the basic cellular processes, and how these are altered in cancer cells, can ultimately provide a background for rational therapies. Bringing together the state-of-the-art contributions of international experts, Systems Biology of Cancer proposes an ultimate research goal for the whole scientific community: exploiting systems biology to generate in-depth knowledge based on blueprints that are unique to each type of cancer. Readers are provided with a realistic view of what is known and what is yet to be uncovered on the aberrations in the fundamental biological processes, deregulation of major signaling networks, alterations in major cancers and the strategies for using the scientific knowledge for effective diagnosis, prognosis and drug discovery to improve public health.
With over 200 types of cancer diagnosed to date, researchers the world over have been forced to rapidly update their understanding of the biology of cancer. In fact, only the study of the basic cellular processes, and how these are altered in cancer cells, can ultimately provide a background for rational therapies. Bringing together the state-of-the-art contributions of international experts, Systems Biology of Cancer proposes an ultimate research goal for the whole scientific community: exploiting systems biology to generate in-depth knowledge based on blueprints that are unique to each type of cancer. Readers are provided with a realistic view of what is known and what is yet to be uncovered on the aberrations in the fundamental biological processes, deregulation of major signaling networks, alterations in major cancers and the strategies for using the scientific knowledge for effective diagnosis, prognosis and drug discovery to improve public health.
With over 200 types of cancer diagnosed to date, researchers the world over have been forced to rapidly update their understanding of the biology of cancer. In fact, only the study of the basic cellular processes, and how these are altered in cancer cells, can ultimately provide a background for rational therapies. Bringing together the state-of-the-art contributions of international experts, Systems Biology of Cancer proposes an ultimate research goal for the whole scientific community: exploiting systems biology to generate in-depth knowledge based on blueprints that are unique to each type of cancer. Readers are provided with a realistic view of what is known and what is yet to be uncovered on the aberrations in the fundamental biological processes, deregulation of major signaling networks, alterations in major cancers and the strategies for using the scientific knowledge for effective diagnosis, prognosis and drug discovery to improve public health.
With over 200 types of cancer diagnosed to date, researchers the world over have been forced to rapidly update their understanding of the biology of cancer. In fact, only the study of the basic cellular processes, and how these are altered in cancer cells, can ultimately provide a background for rational therapies. Bringing together the state-of-the-art contributions of international experts, Systems Biology of Cancer proposes an ultimate research goal for the whole scientific community: exploiting systems biology to generate in-depth knowledge based on blueprints that are unique to each type of cancer. Readers are provided with a realistic view of what is known and what is yet to be uncovered on the aberrations in the fundamental biological processes, deregulation of major signaling networks, alterations in major cancers and the strategies for using the scientific knowledge for effective diagnosis, prognosis and drug discovery to improve public health.
With over 200 types of cancer diagnosed to date, researchers the world over have been forced to rapidly update their understanding of the biology of cancer. In fact, only the study of the basic cellular processes, and how these are altered in cancer cells, can ultimately provide a background for rational therapies. Bringing together the state-of-the-art contributions of international experts, Systems Biology of Cancer proposes an ultimate research goal for the whole scientific community: exploiting systems biology to generate in-depth knowledge based on blueprints that are unique to each type of cancer. Readers are provided with a realistic view of what is known and what is yet to be uncovered on the aberrations in the fundamental biological processes, deregulation of major signaling networks, alterations in major cancers and the strategies for using the scientific knowledge for effective diagnosis, prognosis and drug discovery to improve public health.
Ever since the theory of natural selection was proposed, the study of how characters are inherited across generations has become a principal paramount in biology. These studies have focused on deciphering how phenotypic variation and plasticity across generations contribute to population maintenance and evolution. In this regard, studying how the experience of environmental conditions of a parental population influences offspring phenotypic characteristics through epigenetic processes has gained substantial attention in the past decades. In particular, the mechanisms underpinning this type of transgenerational acclimation include maternal provisioning, microbiome transfer, inheritance of epigenetic markers (e.g., DNA methylation, small RNAs, and histone modifications), and behavioral and cultural processes. These phenomena can result in the programming of the next generation and influence their survival and adaptability to changing environmental conditions. To better understand this topic, in the first part of this chapter I will introduce the reader to the scientific framework on which transgenerational epigenetic programming, and non-genetic inheritance in general, finds its roots. In the second part, I revised the concepts of ‘epigenetics’, ‘transgenerational inheritance’, and, ‘programming’, with the purpose of building a solid ground on which we can base an integrated and deeper discussion in the subsequent sections. The third part of this chapter is focused on discussing the connection between these three concepts, as well as to delve into the tight, but complex, link between ‘transgenerational epigenetic programming’ and developmental biology. After revieing the concept and providing examples of its complexity, I discuss the potential evolutionary implications of transgenerational epigenetic programming in the fourth part of the chapter. Finally, I posit a list of topics and approaches that warrant further research in this scientific field and provide future directions that will help to elucidate knowledge gaps.
Genetic epidemiology is a research discipline that combines genetics, molecular biology, epidemiology, statistics and bioinformatics to investigate the role of genes, the environment and their interaction in the expression of quantitative and qualitative traits and diseases in the population at large. Genetic epidemiologists often leverage population‐based family, case–control, and cohort research designs, including many with a longitudinal data collection scheme. However, characterising the influence of genes and the environment traits and diseases is complicated because most traits and diseases are influenced by a number of genetic and nongenetic factors. In addition to the problems associated with the characterisation of the genetic and environmental factors influencing traits and diseases due to the complex, multifactorial and context‐dependent pathophysiological basis of most traits and diseases, a number of issues associated with the genetic structure of human populations also complicate relevant analyses. Genetic epidemiologists attempt to deal with these issues in many ways. As the current biomedical research area era involving high‐throughput and data‐intensive assays evolves, new fields (e.g. metabolomics, epigenomics and megagenomics), technologies (e.g. high‐throughput sequencing, microarrays and mass spectrometry) and statistical approaches will be brought into genetic epidemiology, enabling more comprehensive ‘system‐level’ approaches to characterising the roles of the environment and inherited factors in disease risk, incidence, prevalence and response to therapy.
Key Concepts
Genetic epidemiologists investigate the role of genes, the environment and their interaction between the aetiology and population‐level incidence and prevalence of health‐related traits and diseases within families and in the population at large.
Factors at both the population and the individual or pathophysiological level contribute to the complexity of complex diseases, making it difficult to identify and characterise their determinants.
The main approaches taken by genetic epidemiologists for discovering genes influencing diseases and traits are family‐based linkage and population‐based association studies.
Once a variant gene has been identified, genetic epidemiologists characterise the effect of that gene on the disease burden or trait distribution in the population using a number of approaches, such as cataloguing its frequency in different populations, examining environmental factors that exacerbate or ameliorate its effects and assessing its origins and its typical effect on the time course of, for example, disease expression among individuals.
By integrating data from multiple high‐throughput biomedical assays (e.g. data from epigenomics, metabolomics, proteomics and metabolomics), genetic epidemiologists can apply ‘system‐level’ approaches to understand how various factors contribute to interaction in the expression of health‐related traits and diseases.
Epigenetics is likely to play a role in the mediation of the effects of genes and environment in risk for many non-communicable diseases (NCDs). The Developmental Origins of Health and Disease (DOHaD) theory presents unique opportunities regarding the possibility of early life interventions to alter the epigenetic makeup of an individual, thereby modifying their risk for a variety of NCDs. While it is important to determine how we can lower the risk of these NCDs, it is equally important to understand how the public’s knowledge and opinion of DOHaD and epigenetic concepts may influence their willingness to undertake such interventions for themselves and their children. In this review, we provide an overview of epigenetics, DOHaD, NCDs, and the links between them. We explore the issues surrounding using epigenetics to identify those at increased risk of NCDs, including the concept of predictive testing of children. We also outline what is currently understood about the public’s understanding and opinion of epigenetics, DOHaD, and their relation to NCDs. In doing so, we demonstrate that it is essential that future research explores the public’s awareness and understanding of epigenetics and epigenetic concepts. This will provide much-needed information which will prepare health professionals for the introduction of epigenetic testing into future healthcare.
Introduction: Among the factors that may be associated with the re-expression gamma-globin in adults is the methylation pattern of the promoter region. The study aimed to determine the association between promoter methylation pattern of the gamma-globin gene in the carriers and affected beta-thalassemia individuals and its expression levels.
Methods: This study has been done as a case control- study. After taking blood samples from 30 patients and beta-thalassemia carriers and affected patients with fetal hemoglobin elevated as well as 30 normal individuals, genomic DNA was extracted. Six CpG sites of the promoter region and exon1 of the gamma-globin gene were analyzed by the bisulfite sequencing analysis method. Statistical analysis was carried out using a t-test. The values of p ≤ 0.05 were considered significant for comparing two studied groups. Data were analyzed using SPSS version 16 software.
Results: In this study, hypomethylation of the gamma-globin promoter region in the patients and carriers compared to showed a significant differences in three CpG sites +6, -53 and -162, respectively (p
The issue of male germ line mutagenesis and the effects on developmental defects in the next generation has become increasingly high profile over recent years. Mutations are thought to be becoming more prevalent as a result of: exposure to chemicals in the environment, anti cancer regimes that use genotoxic agents and assisted conception techniques. In addition to the increasing frequency of mutations in the general population, attention is also being given to the effects of epigenetic events on future generations. Male-mediated Developmental Toxicity discusses these issues comprehensively and includes further analysis on the fundamental mechanisms of mutations. With both clinical and experimental sections, written by leading experts in the field, this book will appeal to both medical practitioners and researchers.
Alcohol use disorder (AUD) is a leading cause of morbidity and mortality. Despite AUD's substantial contributions to lost economic productivity and quality of life, there are only a limited number of approved drugs for treatment of AUD in the United States. This chapter will update progress made on the epigenetic basis of AUD, with particular focus on histone post-translational modifications and DNA methylation and how these two epigenetic mechanisms interact to contribute to neuroadaptive processes leading to initiation, maintenance and progression of AUD pathophysiology. We will also evaluate epigenetic therapeutic strategies that have arisen from preclinical models of AUD and epigenetic biomarkers that have been discovered in human populations with AUD.
Cancer is a major global public health problem. Among different environmental and lifestyle factors contributing to cancer risk, diet is a key one. On the one hand, obesity and increased consumption of red and processed meat, ethanol, sugar and saturated fatty acids are associated with increased cancer risk. On the other hand, consumption of micronutrients such as vitamin D, selenium, zinc, folate and bioactive compounds from fruits and vegetables is associated with decreased risk.
Written by an influential, international team of experts, this book presents and discusses current topics on nutrition and cancer prevention. It covers both nutritional influences on different cancers plus specific chapters on the commonly occurring cancers. Nutritional genomics-based studies show that some dietary components modulate carcinogenesis through complex cellular and molecular mechanisms. A better understanding of these different cellular and molecular mechanisms is needed to establish efficient dietary recommendations for cancer prevention. This book will provide such an understanding, serving as an important book for all those working in nutritional health, food science and cancer research.
The precise cause of neuronal death in Huntington's disease (HD) is unknown. Although no single specific protein-protein interaction of mutant huntingtin has emerged as the pathologic trigger, transcriptional dysfunction may contribute to the neurodegeneration observed in HD. Pharmacological treatment using the histone deacetylase inhibitor sodium butyrate to modulate transcription significantly extended survival in a dose-dependent manner, improved body weight and motor performance, and delayed the neuropathological sequelae in the R6/2 transgenic mouse model of HD. Sodium butyrate also increased histone and Specificity protein-1 acetylation and protected against 3-nitropropionic acid neurotoxicity. Microarray analysis showed increased expression of alpha- and beta-globins and MAP kinase phosphatase-1 in sodium butyrate-treated R6/2 mice, indicative of improved oxidative phosphorylation and transcriptional regulation. These findings strengthen the hypothesis that transcriptional dysfunction plays a role in the pathogenesis of HD and suggest that therapies aimed at modulating transcription may target early pathological events and provide clinical benefits to HD patients.
Background: Methylation of genomic DNA is dependent on an adequate supply of folate coenzymes. Previous data support the hypothesis that abnormal DNA methylation plays an integral role in carcinogenesis. To date, no studies assessing the effect of inadequate folate status on DNA methylation in older women (aged >63 y) have been reported.
Objective: The effect of moderate folate depletion followed by folate repletion on leukocyte genomic DNA methylation was investigated in elderly women (aged 60–85 y) to evaluate whether DNA methylation could be used as a functional indicator of folate status.
Design: Healthy, postmenopausal women (n = 33) consumed a moderately folate-depleted diet (118 μg folate/d) for 7 wk, followed by 7 wk of folate repletion with 200 or 415 μg/d, each provided as 2 different dietary treatments for a total of 4 treatment groups (n = 30). Leukocyte DNA methylation was determined on the basis of the ability of DNA to incorporate [³H]methyl groups from labeled S-adenosylmethionine in an in vitro assay.
Results: Incorporation of [³H]methyl groups increased significantly (P = 0.0025) in response to folate depletion, suggesting undermethylation of DNA. No significant changes were detected in [³H]methyl incorporation in any group over the 7-wk repletion period compared with postdepletion values.
Conclusions: DNA methylation status may be used as a functional indicator of moderately depleted folate status. The slow response to the repletion diets observed suggests that normalization of DNA methylation after moderate folate depletion may be delayed in older women.
Complementary sets of genes are epigenetically silenced in male and female gametes in a process termed genomic imprinting.
TheDnmt3L gene is expressed during gametogenesis at stages where genomic imprints are established. Targeted disruption ofDnmt3L caused azoospermia in homozygous males, and heterozygous progeny of homozygous females died before midgestation. Bisulfite
genomic sequencing of DNA from oocytes and embryos showed that removal of Dnmt3L prevented methylation of sequences that are
normally maternally methylated. The defect was specific to imprinted regions, and global genome methylation levels were not
affected. Lack of maternal methylation imprints in heterozygous embryos derived from homozygous mutant oocytes caused biallelic
expression of genes that are normally expressed only from the allele of paternal origin. The key catalytic motifs characteristic
of DNA cytosine methyltransferases have been lost from Dnmt3L, and the protein is more likely to act as a regulator of imprint
establishment than as a DNA methyltransferase.
We show that the 3' boundary of the chicken -globin locus bears striking structural similarities to the 5' boundary. In erythroid cells a clear transition in DNase I sensitivity of chromatin at the 3' end of the locus is observed, the location of this transition is marked by a constitutive DNase I hypersensitive site (HS), and DNA spanning this site has the enhancer-blocking capacity of an insulator. This HS contains a binding site for the transcription factor CTCF. As in the case of the 5' insulator, the CTCF site is both necessary and sufficient for the enhancer-blocking activity of the 3' boundary. The position of this insulator is consistent with our proposal that it may function to maintain the distinct regulatory programs of the globin genes and their closely appended 3' neighbor, an odorant receptor gene. We conclude that both boundaries of the chicken -globin domain are capable of playing functionally similar roles and that the same protein is a necessary component of the molecular mechanism through which these boundaries are defined.
Transplantation of pronuclei between one-cell-stage embryos was used to construct diploid mouse embryos with two female pronuclei ( biparental gynogenones ) or two male pronuclei ( biparental androgenones ). The ability of these embryos to develop to term was compared with control nuclear-transplant embryos in which the male or the female pronucleus was replaced with an isoparental pronucleus from another embryo. The results show that diploid biparental gynogenetic and androgenetic embryos do not complete normal embryogenesis, whereas control nuclear transplant embryos do. We conclude that the maternal and paternal contributions to the embryonic genome in mammals are not equivalent and that a diploid genome derived from only one of the two parental sexes is incapable of supporting complete embryogenesis.
To determine the molecular basis of Prader-Willi syndrome (PWS) and Angelman syndrome (AS), we have isolated new transcripts from chromosome 15q11-q13. Two novel transcripts located within 300 kilobases telomeric to the small nuclear ribonucleoprotein-associated polypeptide N gene (SNRPN) were paternally expressed in cultured cells, along with SNRPN, defining a large imprinted transcriptional domain. In three PWS patients (two sibs), small deletions remove a differentially methylated CpG island containing a newly described 5' exon alpha of SNRPN, and cause loss of expression for the three imprinted transcripts and altered methylation over hundreds of kilobases. The smallest PWS deletion is familial and asymptomatic with maternal transmission. Our data imply the presence of a paternal imprinting control region near exon alpha.
MeCP2 is a chromosomal protein which binds to DNA that is methylated at CpG. In situ immunofluorescence in mouse cells has shown that the protein is most concentrated in pericentromeric heterochromatin, suggesting that MeCP2 may play a role in the formation of inert chromatin. Here we have isolated a minimal methyl-CpG binding domain (MBD) from MeCP2. MBD is 85 amino acids in length, and binds exclusively to DNA that contains one or more symmetrically methylated CpGs. MBD has negligable non-specific affinity for DNA, confirming that non-specific and methyl-CpG specific binding domains of MeCP2 are distinct. In vitro footprinting indicates that MBD binding can protect a 12 nucleotide region surrounding a methyl-CpG pair, with an approximate dissociation constant of 10(-9) M.
The X and Y chromosomes that maintain human dimorphism are thought to have descended from a single progenitor, with the Y chromosome becoming largely depleted of genes. A number of genes, however, retain copies on both X and Y chromosomes and escape the inactivation that affects most X-linked genes in somatic cells. Many of those genes are present in two pseudoautosomal regions (PARs) at the termini of the short (p) and long (q) arms of the sex chromosomes. For both PARs, pairing facilitates the exchange of information, ensuring the homogenisation of X and Y chromosomal material in these regions. We report here a strikingly different regulation of expression of a gene in Xq PAR. Unlike all Xp PAR genes studied so far, a synaptobrevin-like gene, tentatively named SYBL1, undergoes X inactivation. In addition, it is also inactive on the Y chromosome, thereby maintaining dosage compensation in an unprecedented way.
The way we quantify the human genome has changed markedly. The estimated percentage of the genome derived from
retrotransposition has increased (now 45%; refs. 1,2), as have the estimates for alternative splicing (now 41–60% of multiexon
genes)3,4, antisense transcription (now 10–20% of genes)5,6 and non–protein coding RNA (now ∼7% of full-length cDNAs)7.
Concomitantly, the estimated number of protein-coding genes (now ∼24,500) has decreased8. These numbers support an RNAcentric
view of evolution in which phenotypic diversity arises through extensive RNA processing and widespread RNA-directed
rewriting of DNA enables dissemination of ‘selfish’ RNAs associated with successful outcomes9. The numbers also indicate
important roles for sense-antisense transcription units (SATs) and coregulatory RNAs (coRNAs) in directing the read-out of genetic
information, in reconciling different regulatory inputs and in transmitting epigenetic information to progeny. Together, the actions
of reading, ’riting, ’rithmetic and replication constitute the four Rs of RNA-directed evolution.
A number of recent clinical and molecular observations in major psychosis indicate that epigenetic factors may be operational in the origin of major mental illness. This article further develops the idea that epigenetic factors may play an etiopathogenic role in schizophrenia and bipolar affective disorder. The putative role of epigenetic factors is shown by the epigenetic interpretation of genetic association studies of the genes for serotonin 2A (HTR2A) and the dopamine D3 (DRD3) receptors in schizophrenia. The idea of epigenetic polymorphism of genetic alleles is introduced, and it is argued that epigenetic variation may explain a number of controversial and unclear findings in allelic and genotypic association studies of HTR2A and DRD3. In linkage analyses of multiplex families with bipolar affective disorder (BPAD), different loci on chromosome 18 indicated co-segregation of alleles of one parental sex with the disease phenotype, and this finding implies that the epigenetic mechanism of genomic imprinting may be involved. Evidence for genomic imprinting provides the background for epigenetic cloning of BPAD risk factors by searching for differentially modified genes on chromosome 18. Finally, epigenetic studies could be relevant to the better understanding of the molecular action of antipsychotic medications. In addition to this, if epimutations are detected in major psychosis, epigenetic treatment directed at correction of epigenetic status of a specific brain gene may eventually be developed.
Summary In severe MTHFR deficiency with neonatal or adolescent onset, 9 rare mutations have been identified. In mild MTHFR deficiency with thermolabile enzyme, a single common mutation (an alanine-to-valine substitution) is involved, but a genetic-nutrient interactive effect is required to produce mild hyperhomocysteinaemia. This interactive effect has been proposed to be a risk factor for arteriosclerosis and for neural-tube defects. Large-scale studies are required for confirmation of the role of MTHFR in these multifactorial processes as well as to assess its role in other folate-dependent disorders.
The recessive autosomal disorder known as ICF syndrome (for immunodeficiency, centromere instability and facial anomalies; Mendelian Inheritance in Man number 242860) is characterized by variable reductions in serum immunoglobulin levels which cause most ICF patients to succumb to infectious diseases before adulthood. Mild facial anomalies include hypertelorism, low-set ears, epicanthal folds and macroglossia. The cytogenetic abnormalities in lymphocytes are exuberant: juxtacentromeric heterochromatin is greatly elongated and thread-like in metaphase chromosomes, which is associated with the formation of complex multiradiate chromosomes. The same juxtacentromeric regions are subject to persistent interphase self-associations and are extruded into nuclear blebs or micronuclei. Abnormalities are largely confined to tracts of classical satellites 2 and 3 at juxtacentromeric regions of chromosomes 1, 9 and 16. Classical satellite DNA is normally heavily methylated at cytosine residues, but in ICF syndrome it is almost completely unmethylated in all tissues. ICF syndrome is the only genetic disorder known to constitutive abnormalities of genomic methylation Here we show that five unrelated ICF patients have mutations in both alleles of the gene that encodes DNA methyltransferase 3B (refs 5, 6). Cytosine methylation is essential for the organization and stabilization of a specific type of heterochromatin, and this methylation appears to be carried out by an enzyme specialized for the purpose.
This chapter briefly describes the well-characterized syndromes associated with UPD such as neonatal transient diabetes mellitus (TNDM), Silver-Russell (SRS), Beckwith-Wiedemann (BWS), Prader-Willi (PWS), and Angelman syndromes (AS). In addition, recently characterized phenotypes associated with UPD, such as maternal and paternal UPD14 syndromes are described. Finally, evidence for maternal UPD2, and maternal UPD16 syndromes is presented.
A new study shows that a deletion-induced aberrant antisense transcript from a neighboring gene leads to methylation and silencing of the intact gene HBA2 (encoding human alpha-globin A2) in a family with alpha-thalassemia. Are there other chromosomal rearrangements that might turn off genes by such antisense-mediated cis-acting methylation?
Expression of imprinted genes is dependent on their parental origin. This is reflected in the heritable differential methylation of parental alleles. The gametic imprints are however reversible as they do not endure for more than one generation. To investigate if the epigenetic changes in male and female germ line are similar or not, we derived embryonic germ (EG) cells from primordial germ cells (PGCs) of day 11.5 and 12.5 male and female embryos. The results demonstrate that they have an equivalent epigenotype. First, chimeras made with EG cells derived from both male and female embryos showed comparable fetal overgrowth and skeletal abnormalities, which are similar to but less severe than those induced by androgenetic embryonic stem (ES) cells. Thus, EG cells derived from female embryos resemble androgenetic ES cells more than parthenogenetic cells. Furthermore, the methylation status of both alleles of a number of loci in EG cells was similar to that of the paternal allele in normal somatic cells. Hence, both alleles of Igf2r region 2, Peg1/Mest, Peg3, Nnat were consistently unmethylated in EG cells as well as in the primary embryonic fibroblasts (PEFs) rescued from chimeras. More strikingly, both alleles of p57kip2 that were also unmethylated in EG cells, underwent de novo methylation in PEFs to resemble a paternal allele in somatic cells. The exceptions were the H19 and Igf2 genes that retained the methylation pattern in PEFs as seen in normal somatic tissues. These studies suggest that the initial epigenetic changes in germ cells of male and female embryos are similar.
Bei Säugerkeimzellen, Zygoten und Embryos in frühen Stadien kommt der epigenetischen Neuprogammierung eine außergewöhnlich wichtige Rolle in der Regulation der Genomfunktionen in entscheidenden Entwicklungsstadien zu. Die epigenetische Neuprogrammierung in Keimzellen löscht zuerst die Imprinting-Markierungen und Epi-Mutationen und stellt dann geschlechtsspezifische Markierungen (genomische Prägung) wieder her. Die vorliegende Arbeit bezieht sich auf das Löschen epigenetischer Modifikationen in primordialen Mauskeimzellen (primordial germ cells (PGCs)) zwischen dem 10.5 bis 13.5 Tag nach der Befruchtung. Entgegen früheren Annahmen zeigen unsere Ergebnisse, daß primordiale Mauskeimzellen (PGCs) beim Eintritt in die embryonalen Keimdrüsen noch immer DNS Methylierungsmarker besitzen, die ähnlich dem Marker in somatischen Zellen sind. Kurz nach dem Eintritt in die Keimdrüsen werden die DNS Methylierungsmarker, die in Verbindung mit geprägten und nicht geprägten Genen stehen, gelöscht. Für die Mehrzahl der Gene beginnt die Löschung der Marker in männlichen und weiblichen Embryos gleichzeitig und ist innerhalb eines Entwicklungstages abgeschlossen. Diese Kinetik deutet auf einen aktiven Demethylierungsprozess hin, initiiert durch ein somatisches Signal, ausgehend von der embryonalen Keimdrüse. Der Zeitpunkt der Neuprogrammierung in den primordialen Keimzellen ist entscheidend, da er sicherstellt, daß Keimzellen beiden Geschlechts einen epigenetisch äquivalenten Status erhalten, bevor sie geschlechtsspezifisch ausdifferenzieren und anschließend neu elterlich geprägt werden. Vollständiges Verständnis des Prozesses der Neuprogrammierung der Keimzellen ist nicht nur im Hinblick auf genomisches Imprinting wichtig, sondern auch für die Erforschung von Mechanismen für die Wiederherstellung von omnipotenten Zellen bei Klonierung und Stammzellenerhaltung.
The synthesis of connections between two or more different carbon nanotubes is an important step in the development of carbon nanotube-based electronic devices and circuits. But this is difficult to achieve using conventional methods to grow carbon nanotubes because the straight tube structure cannot be controllably altered along its length. Various ideas for post-growth modifications have been suggested, but these have been hard to implement and are prone to defects. Here we use nano-structured template channels to grow individual Y-junction carbon-nanotube heterostructures by the pyrolysis of acetylene with cobalt catalysis.
Gene targeting in embryonic stem (ES) cells has been used to mutate the murine DNA methyltransferase gene. ES cell lines homozygous for the mutation were generated by consecutive targeting of both wild-type alleles; the mutant cells were viable and showed no obvious abnormalities with respect to growth rate or morphology, and had only trace levels of DNA methyltransferase activity. A quantitative end-labeling assay showed that the level of m5C in the DNA of homozygous mutant cells was about one-third that of wild-type cells, and Southern blot analysis after cleavage of the DNA with a methylation-sensitive restriction endonuclease revealed substantial demethylation of endogenous retroviral DNA. The mutation was introduced into the germline of mice and found to cause a recessive lethal phenotype. Homozygous embryos were stunted, delayed in development, and did not survive past mid-gestation. The DNA of homozygous embryos showed a reduction of the level of m5C similar to that of homozygous ES cells. These results indicate that while a 3-fold reduction in levels of genomic m5C has no detectable effect on the viability or proliferation of ES cells in culture, a similar reduction of DNA methylation in embryos causes abnormal development and embryonic lethality.
We are studying mice that carry a targeted disruption of the gene encoding insulin-like growth factor II (IGF-II). Transmission of this mutation through the male germline results in heterozygous progeny that are growth deficient. In contrast, when the disrupted gene is transmitted maternally, the heterozygous offspring are phenotypically normal. Therefore, the difference in growth phenotypes depends on the type of gamete contributing the mutated allele. Homozygous mutants are indistinguishable in appearance from growth-deficient heterozygous siblings. Nuclease protection and in situ hybridization analyses of the transcripts from the wild-type and mutated alleles indicate that only the paternal allele is expressed in embryos, while the maternal allele is silent. An exception is the choroid plexus and leptomeninges, where both alleles are transcriptionally active. These results demonstrate that IGF-II is indispensable for normal embryonic growth and that the IGF-II gene is subject to tissue-specific parental imprinting.
Mouse genetic studies using Robertsonian and reciprocal translations have shown that certain autosomal regions of loci are subject to a parental germ line imprint, which renders maternal and paternal copies functionally inequivalent in the embryo or later stages of development. Duplication of maternal or paternal copies with corresponding paternal/maternal deficiencies in chromosomally balanced zygotes causes various effects. These range from early embryonic lethalities through to mid-fetal and neonatal lethalities, and in some instances viable young with phenotypic effects are obtained. Eight to nine chromosomal regions that give such imprinting effects have been identified. Six to seven of these regions are located in only three chromosomes (2, 7 and 17). The two other regions are located in chromosomes 6 and 11. Maternal and paternal disomies for each of four other chromosomes (1, 5, 9 and 14) have been recovered with different frequencies, but the possibility that this may be due to imprinting has yet to be supported by follow-up studies on regions of the chromosomes concerned. No clear evidence of genetic-background modifications of the imprinting process have been observed in these mouse genetic experiments.
The mammalian X chromosome is also subject to imprinting, as demonstrated by the non-random, paternal X-inactivation in female mouse extra-embryonic tissues and in the somatic cells of marsupial females. There is also the opposite bias towards inactivation of the maternal X in the somatic cells of female mice. On the basis that both X-chromosome inactivation and autosomal chromosome imprinting may be concerned with gene regulation, it is suggested that evidence from X-chromosome inactivation studies may help to elucidate factors underlying the imprinting of autosomes. The relevant aspects of X-inactivation are summarized.
Genomic imprinting appears to be a ubiquitous process in mammals involving many chromosome segments whose affects are dependent on their parental origin. One of the challenges for clinical geneticists is to determine which disorders are manifesting imprinting effects and which families are affected. Re-evaluation of cases of chromosomal abnormalities and family histories of disease manifestations should give important clues. Examination of the regions of human chromosomes homologous to mouse imprinted chromosomal regions may yield useful information. Cases of discordance in monozygous twins may also provide important insights into imprinted modification of diseases.
One hundred and two benign, mature ovarian teratomas and two immature, malignant teratomas were karyotyped and scored for centromeric heteromorphisms as part of an ongoing project to determine the chromosomal karyotype and the genetic origin of ovarian teratomas and to assess their utility for gene-centromere mapping. Karyotypic analysis of the benign cases revealed 95 46,XX teratomas and 7 chromosomally abnormal teratomas (47,XXX, 47,XX,+8 [two cases], 47,XX,+15, 48,XX,+7,+12 91,XXXX,-13 [mosaic], 47,XX,-15,+21,+mar). Our study reports on the first cases of tetraploidy and structural rearrangement in benign ovarian teratomas. The two immature cases had modal chromosome numbers of 78 and 49. Centromeric heteromorphisms that were heterozygous in the host were homozygous in 65.2% (n = 58) of the benign teratomas and heterozygous in the remaining 34.8% (n = 31). Chromosome 13 heteromorphisms were the most informative, with 72.7% heterozygosity in hosts. The cytogenetic data indicate that 65% of teratomas are derived from a single germ cell after meiosis I and failure of meiosis II (type II) or endoreduplication of a mature ovum (type III); 35% arise by failure of meiosis I (type I) or mitotic division of premeiotic germ cells (type IV).
In a considerable number of genetic disorders in the human, the phenotypic expression of the disease can depend on maternal or paternal inheritance of the mutation. It is suggested that genomic imprinting, an epigenetic process that marks maternal and paternal chromosomes in mammals, is involved in such parental effects.
A female with cystic fibrosis and short stature was investigated for molecular or cytogenetic abnormalities that might explain the combined phenotype. Analysis with polymorphic DNA markers indicated that the father did not contribute alleles to the propositus for markers near the CF locus or for centromeric markers on chromosome 7. High-resolution cytogenetic analysis was normal, and the result could not be explained on the basis of nonpaternity or a submicroscopic deletion. All of the data indicate that the propositus inherited two identical copies of maternal sequences for much or all of chromosome 7. The occurrence of uniparental disomy could be explained by models postulating postfertilization error, gamete complementation, monosomic conception with subsequent chromosome gain, or trisomic conception followed by chromosome loss. Uniparental disomy in an individual with a normal chromosome analysis is a novel mechanism for the occurrence of human genetic disease.
Although both parental sexes contribute equivalent genetic information to the zygote, in mammals this information is not necessarily functionally equivalent. Diploid parthenotes possessing two maternal genomes are generally inviable, embryos possessing two paternal genomes in man may form hydatidiform moles, and nuclear transplantation experiments in mice have shown that both parental genomes are necessary for complete embryogenesis. Not all of the genome is involved in these parental effects, however, because zygotes with maternal or paternal disomy for chromosomes 1, 4, 5, 9, 13, 14 and 15 of the mouse survive normally. On the other hand, only the maternal X chromosome is active in mouse extraembryonic membranes, maternal disomy 6 is lethal, while non-complementation of maternal duplication/paternal deficiency or its reciprocal for regions of chromosome 2, 8 and 17 has been recognized. We report that animals with maternal duplication/paternal deficiency and its reciprocal for each of two particular chromosome regions show anomalous phenotypes which depart from normal in opposite directions, suggesting a differential functioning of gene loci within these regions. A further example of non-complementation lethality is also reported.
Using an historical approach, this article describes how genetic studies have elucidated the two entities into which the syndrome of hydatidiform mole can now be divided. Partial moles are triploid, have a maternal chromosomal set, and are associated with the presence of a fetus. Complete moles lack a fetus and are always diploid and androgenetic in origin, having two sets of paternal chromosomes. They are most often XX and homozygous, the most likely origin being by duplication of a haploid sperm. About 4% of complete moles have been shown to by XY and heterozygous, the most likely origin being by dispermy. The frequency of partial and complete mole observed depends on the method of ascertainment. Among spontaneous abortions, partial moles are more common than complete moles, but among cases having an elective termination of pregnancy because of a prior diagnosis of hydatidiform mole, complete mole is the more common. Patients with either type of mole may require treatment for persistent trophoblastic activity. More prospective studies of cases in which the type of mole has been confirmed by genetic studies are required in order to find out whether (a) patients with complete moles are more likely than those with partial moles to require treatment for persistence of trophoblastic activity after evacuation; and (b) heterozygous complete moles have a different prognosis from the point of view of malignant sequelae than homozygous complete moles.
In eukaryotic DNA, 50-90% of the dinucleotide sequence C-G is methylated. Most methylated sites are apparently placed at fixed locations in the genome and this methylation pattern is faithfully inherited from generation to generation1. Holliday and Pugh2 and Riggs3 have suggested that methyl moieties are inherited in a semi-conservative fashion during DNA replication, and this model has been confirmed by experiments in which methylated DNA was integrated into mouse L-cells following DNA-mediated gene transfer4-6. For this mechanism to operate, two basic requirements must be satisfied: (1) methyl moieties must be symmetrically placed on both strands of the DNA7,8 and (2) the cellular methylase should be specific for the hemi-methylated substrate present during DNA replication. Here we demonstrate conclusively that the preferred substrate in vitro for the mouse ascites DNA methylase is indeed hemi-methylated DNA. Furthermore, this enzyme seems to methylate exclusively cytosine residues located at the dinucleotide C-G
The expression of the H19 gene is governed by parental imprinting in mammals. H19, an unusual gene encoding an RNA with no known function, is exclusively expressed from the maternal chromosome. In mouse, it lies 90 kb downstream from the Igf2 gene, which encodes a fetal-specific growth factor, insulin-like growth factor II, and is expressed primarily from the paternally inherited chromosome. In this report we have utilized interspecific hybrid mice to identify male-specific DNA methylation of a 7- to 9-kb domain surrounding the H19 gene and its promoter. This allele-specific methylation could function as a mark to suppress transcription of the H19 paternal allele. Consistent with this proposal, the H19 promoter displayed an open chromatin conformation only on the relatively unmethylated active maternal allele. In contrast, a cell type-specific enhancer that lies outside the methylation domain is hypersensitive to restriction enzyme digestion in nuclei on both maternal and paternal chromosomes. That the allele-specific methylation domain, coupled to the two H19 enhancers, contains all the information necessary for its imprinting was tested by examining two transgenic lines containing an internally deleted H19 transgene. Both displayed paternal-specific methylation of the transgene and maternal-specific expression. Although neither line has been tested in an inbred genetic background, and therefore the action of complex modifiers cannot be formally excluded, the result suggests that the sequences necessary for the imprinting of H19 have been identified.
Recently, probe p13E-11 (D4F104S1) was shown to identify de novo DNA rearrangements, which are associated with the development of facioscapulohumeral muscular dystrophy (FSHD). These rearrangements are likely to become instrumental in cloning the FSHD gene itself. Analysis by pulsed-field gel electrophoresis demonstrates that p13E-11 recognizes two highly polymorphic loci, with HindIII restriction fragments ranging in size from about 30 to 320 kb. Haplotype analysis unambiguously assigned one of the two loci to chromosome 4q35. The detection of identical NotI or NruI fragments with both CEB8 (D4F35S1) and p13E-11 demonstrated that the DNA rearrangements are deletions that are restricted to the HindIII fragments detectable by p13E-11. In two cases, the sizes of the deletion could be established and were found to be 25 and 85 kb in length, respectively. So far, we have been able to define the parental origin of the mutation in seven different patients and have found that in five cases the maternal allele was involved.
The agouti gene normally confers the wild-type coat color of mice. Dominant mutations at the agouti locus result in a pleiotropic syndrome that is characterized by excessive amounts of yellow pigment in the coat, obesity, a non-insulin-dependent diabetic-like condition, and the propensity to form a variety of tumors. Here, we describe a new dominant mutation at the agouti locus in which an intracisternal A-particle (IAP) has integrated in an antisense orientation immediately 5' of the first coding exon of the gene. This mutation, which we have named Aiapy, results in the ectopic expression of the agouti gene through the utilization of a cryptic promoter within the IAP 5' long terminal repeat (LTR). The coat color of Aiapy/-mice ranges from solid yellow to a pigment pattern that is similar to wild type (pseudoagouti), and the expressivity of this mutant phenotype varies with parental inheritance. Those offspring with a yellow coat ectopically express agouti mRNA at high levels and exhibit marked obesity, whereas pseudoagouti mice express agouti mRNA at a very low level and their weights do not differ from wild-type littermates. Data are presented to show that the differential expressivity of the Aiapy allele is correlated with the methylation status of the inserted IAP 5' LTR. These data further support the hypothesis that in dominant yellow mutations at the agouti locus, it is the ubiquitous expression of the wild-type agouti coding sequence that is responsible for the yellow coat color, obesity, diabetes, and tumorigenesis.
Genomic imprinting is a mechanism whereby only one of the two parental alleles is expressed. Loss or relaxation of genomic imprinting has been proposed as an epigenetic mechanism for oncogenesis in a variety of human tumours. Although the mechanism of imprinting is unknown, differential CpG methylation of the parental alleles has been implicated. The human insulin-like growth factor-II (IGF2) gene, which is transcribed from four promoters, P1-P4 (ref. 13), is imprinted in fetal liver but biallelic expression occurs in adult liver. Like most tissues, fetal liver uses primarily promoters P3 and P4 (ref. 17). Adult liver, however, transcribes IGF2 from promoter P1, and it has been suggested that the recruitment of P1 may be responsible for the absence of imprinting in human liver, and in choroid plexus and leptomeninges. We report here that in liver and chondrocytes, IGF2 transcripts from promoter P1 are always derived from both parental alleles, whereas transcripts from promoters P2, P3 and P4 are always from one parental allele. These findings demonstrate that imprinting and a lack of imprinting can both occur within a single gene in a single tissue, suggesting that regional imprinting factors may be important.
Mental retardation and a constellation of congenital malformations not usually associated with Turner syndrome are seen in some females with a mosaic 45,X/46,X,r(X) karyotype. Studies of these females show that the XIST locus on their tiny ring X chromosomes is either not present or not expressed. As XIST transcription is well correlated with inactivation of the X chromosome in female somatic cells and spermatogonia, nonexpression of the locus even when it is present suggests that these chromosomes are transcriptionally active. We examined the transcriptional activity of ring X chromosomes lacking XIST expression (XISTE-), from three females with severe phenotypes. The two tiny ring X chromosomes studied with an antibody specific for the acetylated isoforms of histone H4 marking transcribed chromatin domains were labeled at a level consistent with their being active. We also examined tow of the XISTE- ring chromosomes to determine whether genes that are normally silent on an inactive X are expressed from these chromosomes. Analyses of hybrid cells show that TIMP, ZXDA, and ZXDB loci on the proximal short arm, and AR and PHKA1 loci on the long arm, are well expressed from the tiny ring X chromosome lacking XIST DNA. Studies of the ring chromosome that has XIST DNA but does not transcribe it show that its AR allele is transcribed along with the one on the normal X allele.(ABSTRACT TRUNCATED AT 250 WORDS)
The paternal and maternal genomes are not equivalent and both are required for mammalian development. The difference between the parental genomes is believed to be due to gamete-specific differential modification, a process known as genomic imprinting. The study of transgene methylation has shown that methylation patterns can be inherited in a parent-of-origin-specific manner, suggesting that DNA methylation may play a role in genomic imprinting. The functional significance of DNA methylation in genomic imprinting was strengthened by the recent finding that CpG islands (or sites) in three imprinted genes, H19, insulin-like growth factor 2 (Igf-2), and Igf-2 receptor (Igf-2r), are differentially methylated depending on their parental origin. We have examined the expression of these three imprinted genes in mutant mice that are deficient in DNA methyltransferase activity. We report here that expression of all three genes was affected in mutant embryos: the normally silent paternal allele of the H19 gene was activated, whereas the normally active paternal allele of the Igf-2 gene and the active maternal allele of the Igf-2r gene were repressed. Our results demonstrate that a normal level of DNA methylation is required for controlling differential expression of the paternal and maternal alleles of imprinted genes.
Familial adenomatous polyposis is an inherited disease characterized by multiple colorectal tumors. The diagnosis has classically been based on the detection of multiple colorectal adenomas. The recent identification of germline mutations of the APC gene in patients with familial adenomatous polyposis makes presymptomatic molecular diagnosis possible, but the widespread distribution of the many mutations within this very large gene have heretofore made the search for such mutations impractical. We describe a novel approach that allows molecular genetic diagnosis in the majority of patients with the disease.
We screened 62 unrelated patients from the Johns Hopkins Familial Adenomatous Polyposis Registry for germline APC mutations. Primary screening was accomplished by analysis of protein synthesized in vitro from surrogate APC genes. In addition, the relative amount of transcript from each APC allele was determined with an allele-specific--expression assay.
The protein assay revealed truncated protein in 51 of the 62 patients (82 percent). In 3 of the 11 remaining patients, the allele-specific--expression assay revealed significantly reduced expression of one allele of the APC gene. The use of these two assays in combination successfully identified germline APC mutations in 87 percent of the 62 patients.
The protein and allele-specific--expression assays provide a practical and sensitive method for molecular diagnosis of familial adenomatous polyposis. This approach will facilitate care, allowing routine testing of subjects at risk and genetic confirmation of spontaneous mutations.
The H19 gene produces an abundant developmentally regulated transcript of unknown function in normal embryos. In the mouse it lies on chromosome 7 and is subject to transcriptional regulation by parental imprinting, which results in the maternally inherited gene being expressed and the paternally inherited gene being repressed. Embryos carrying maternal duplication/paternal deficiency for distal chromosome 7 (MatDi7) therefore express a double dose of H19. Here we examine the parental-origin-specific epigenetic modifications that may be involved in this regulation by comparing CpG methylation and nuclease sensitivity of chromatin in MatDi7 embryos with normal littermates. We show that specific sites in the CpG island promoter and 5' portion of the gene are methylated only on the paternal allele. Furthermore, active maternal alleles in chromatin of MatDi7 embryos are more sensitive and accessible to nucleases. Therefore hypermethylation and chromatin compaction in the region of the H19 promoter is associated with repression of the paternally inherited copy of the gene. Most, but not all, of these sites are unmethylated in sperm, with methylation of the paternal promoter occurring after fertilization. These results contrast with our findings for the closely linked and reciprocally imprinted gene encoding insulin-like growth factor II (ref. 4).
There are two biological properties of genomic methylation patterns that can be regarded as established. First, methylation of 5'-CpG-3' dinucleotides within promoters represses transcription, often to undetectable levels. Second, in most cases methylation patterns are subject to clonal inheritance. These properties suit methylation patterns for a number of biological roles, although none of the current hypotheses can be regarded as proved or disproved. One hypothesis suggests that the activity of parasitic sequence elements is repressed by selective methylation. Features of invasive sequences that might allow their identification and inactivation are discussed in terms of the genome defense hypothesis. Identification of the cues that direct de novo methylation may reveal the biological role (or roles) of genomic methylation patterns.
Recent discoveries and rediscoveries in molecular and cell biology, in population and evolutionary biology, and in disease natural history raise new doubts about the ability of genetic analysis alone to predict multifactorial (polygenic) human diseases and other complex phenotypes. These doubts serve to redirect our attention to epigenetic regulation as a second informational system in parallel with the genome. Epigenetic regulation is now viewed by many biologists as a process that includes mechanisms capable of constraining the genome and providing for new patterns of gene expression. Epigenetic networks, both intra- and inter-cellular, provide a basis for nonlinear and chaotic views of cellular and tissue level differentiation and organization, and thus provide a more dynamic approach to understanding the creation of complex phenotypes, even from isogeneic conditions. The reality of regulatory networks within cells inserted, as it were, between genome and phenome, also helps explain the difficulties now encountered when prediction and diagnosis of complex disease omits epigenetic considerations and depends entirely on gene causality.
It is proposed that transgenerational modulation of gene expression might be possible, if the metabolic response of the parent to some physiological or social stress modified imprint setting. Transcription regulators could theoretically mediate this process. The nature of imprinted genes poised, as it were, between a transcriptionally active and silent state, makes them good candidates for incorporation into the evolution of transgenerational adaption systems where coordinated changes in gene expression over the generations is a selective advantage. The coordination of human fetal (head) growth with the existing size of the mother's pelvis is suggested as just such a circumstance. The reduce birth weight of Dutch babies where their grandmothers suffered acute starvation in mid pregnancy, supports the notion of transgenerational adaption to nutrition, as does the secular change (increase) in child growth over the last century. The recent indication that there may be functional polymorphism in the imprinting of the human IGF2 and IGF2R genes suggests these ideas could be explored using association studies at the population and individual level.
In severe MTHFR deficiency with neonatal or adolescent onset, 9 rare mutations have been identified. In mild MTHFR deficiency with thermolabile enzyme, a single common mutation (an alanine-to-valine substitution) is involved, but a genetic-nutrient interactive effect is required to produce mild hyperhomocysteinaemia. This interactive effect has been proposed to be a risk factor for arteriosclerosis and for neural-tube defects. Large-scale studies are required for confirmation of the role of MTHFR in these multifactorial processes as well as to assess its role in other folate-dependent disorders.
Molecular genetic techniques allow investigators to trace chromosomes and genes from parent to child and, in a single individual, from tissue to tissue. These techniques have uncovered a new type of gene control in which the allele from one parent is expressed and the allele from the other parent is not. This differential expression is called genomic imprinting. It may lead to phenotypic differences when inheritance is from the mother versus the father. Genomic imprinting has been observed in a number of disorders having to do with growth, behavior, and abnormal cell growth. It is important to be aware that such a phenomenon exists and to consider it when making diagnoses and determining therapy.