![MECP2 represses Evf2 and Dlx5 expression through antagonism of DLX1/2. Quantitative PCR on cDNA isolated from E13.5 medial ganglionic eminence was performed to determine expression levels of Evf2, Dlx5 and Dlx6. Values are normalized to Actb, and expression compared from different genotypes with respective wild-type littermates (+/+, black). The following mutants (gray) were used: Mecp2null (Mecp2-/y ), Mecp2null; Dlx1/2 +/− [Mecp2-/y with one copy of Dlx1/2 (Anderson et al., 1997b)], Dlx1/2 +/− (heterozygote with one copy of Dlx1/2) and Dlx1/2 −/− (Dlx1/2 null lacking Dlx1 and Dlx2). Mecp2 represses Evf2 and Dlx5, but not Dlx6. Dlx1/2 are activators of Evf2, Dlx5 and Dlx6. Dlx1/2 control of Evf2 and Dlx5 is dose dependent, as removal of one copy (Dlx1/2 +/− ) reduces Evf2 and Dlx5 expression. n=3 each genotype. *P<0.01 (Student's t-test). Error bars represent s.e.m.](https://www.researchgate.net/profile/Ivelisse-Cajigas/publication/257310042/figure/fig1/AS:601653438844962@1520456766919/MECP2-represses-Evf2-and-Dlx5-expression-through-antagonism-of-DLX1-2-Quantitative-PCR_Q320.jpg)
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Evf2 (Dlx6as) lncRNA regulates ultraconserved enhancer methylation and the differential transcriptional control of adjacent genes
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Several lines of evidence suggest that long non-coding RNA (lncRNA)-dependent mechanisms regulate transcription and CpG DNA methylation. Whereas CpG island methylation has been studied in detail, the significance of enhancer DNA methylation and its relationship with lncRNAs is relatively unexplored. Previous experiments proposed that the ultraconserved lncRNA Evf2 represses transcription through Dlx6 antisense (Dlx6as) transcription and methyl-CpG binding protein (MECP2) recruitment to the Dlx5/6 ultraconserved DNA regulatory enhancer (Dlx5/6ei) in embryonic day 13.5 medial ganglionic eminence (E13.5 MGE). Here, genetic epistasis experiments show that MECP2 transcriptional repression of Evf2 and Dlx5, but not Dlx6, occurs through antagonism of DLX1/2 in E13.5 MGE. Analysis of E13.5 MGE from mice lacking Evf2 and of partially rescued Evf2 transgenic mice shows that Evf2 prevents site-specific CpG DNA methylation of Dlx5/6ei in trans, without altering Dlx5/6 expression. Dlx1/2 loss increases CpG DNA methylation, whereas Mecp2 loss does not affect Dlx5/6ei methylation. Based on these studies, we propose a model in which Evf2 inhibits enhancer DNA methylation, effectively modulating competition between the DLX1/2 activator and MECP2 repressor. Evf2 antisense transcription and Evf2-dependent balanced recruitment of activator and repressor proteins enables differential transcriptional control of adjacent genes with shared DNA regulatory elements.
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... In addition to regulating CpG island methylation, the lncRNAs have also been shown to differentially regulate transcription of adjacent genes via their effect on DNA enhancer elements. One such study was published by Berghoff et al. in 2013 where it was shown that lncRNA Evf2 prevents the site specific methylation of Dlx5/6 ultraconserved enhancer at two sites [54]. Such an effect of lncRNA is referred to as the trans effect in contrast to the localized effect of lncRNAs where it is referred to as cis effect. ...
... In addition to regulating CpG island methylation, the lncRNAs have also been shown to differentially regulate transcription of adjacent genes via their effect on DNA enhancer elements. One such study was published by Berghoff et al. in 2013 where it was shown that lncRNA Evf2 prevents the site specific methylation of Dlx5/6 ultraconserved enhancer at two sites [54]. Such an effect of lncRNA is referred to as the trans effect in contrast to the localized effect of lncRNAs where it is referred to as cis effect. ...
DNA, RNA, and the proteins are the major players in the flow of genetic information. Out of these, RNA is the most versatile biomolecule as it exists in multiple forms and each form carries out specified functions in the cell. RNA can be classified into coding and noncoding RNA (ncRNA). The noncoding RNA is further subdivided into long noncoding RNA (>200 nucleotides) and small noncoding RNA (<200 nucleotides). The coding RNA is the one which gets translated into proteins; whereas, the ncRNA is usually responsible for the regulation of gene expression. The ncRNA has been implicated in a number of pathological conditions including cancer, diabetes, neurological disorders and developmental defects. The interplay between ncRNAs and epigenetics often plays a significant role in the onset and progression of some of the aforementioned diseases. This chapter elaborates on the different ways in which epigenetic phenomenon is regulated by ncRNA and the effect of epigenetic modification on the expression of ncRNA.
... LncRNA is a non-protein-coding gene with various biological functions. Studies have shown that lncRNA regulates related signaling pathways and methylation of the related gene promoters for regulating the development cycle of HFs (Berghoff et al., 2013). Some lncRNAs can regulate IF-1 and BMP in the Wnt pathway via epigenetic modifications. ...
... LncRNA is the largest subtype of non-coding RNA, which is mainly distributed in the nucleus and partially in the cytoplasm (Berghoff et al., 2013). This study showed that lncRNA2690 is highly expressed in the nucleus through the nucleo-cytoplasmic separation experiment. ...
Hair follicles (HFs) achieve hair growth and renewal by periodic regeneration. Therefore, exploring the key factors affecting hair growth in rabbits is of great significance for precisely breeding Angora rabbits and improving the competitiveness of the rabbit industry. Based on the results of our previous studies, lncRNA2690 was differentially expressed in the HF cycle using lncRNA‐Seq, and the full‐length sequence was annotated by bioinformatics analysis. The lncRNA2690 is 363 nt long and is found on chromosome 14 from 163 321 514 to 163 321 872. The lncRNA2690 was predicted to not have the coding ability through open reading frame and CPC2, and the nuclear–cytoplasmic separation experiment showed the lncRNA2690 to be highly expressed in the nucleus (p < 0.01). The expression pattern of lncRNA2690 was further analyzed in the different HF development stages of Angora rabbits using quantitative real‐time PCR. The results showed that lncRNA2690 was periodically expressed in HF development, and the expression level was found to be high in the HF resting phases. The overexpression and knockdown of lncRNA2690 were found to significantly upregulate and downregulate the expression of the genes WNT2, CCND1, BMP2, LEF1, and SIAH1 in the rabbit dermal papilla cells (p < 0.01), promoting cell apoptosis and inhibiting cell proliferation (p < 0.01). This indicated that lncRNA2690 negatively regulates the periodic regeneration of the HFs in rabbits. These results provide a basis for the further study of lncRNA2690 in the HF growth cycle of Angora rabbits.
... We identified one of the hub lncRNAs, TCONS_00093062 ( = DLX6-AS1), in human neocortical areas (C8) being co-expressed with the genes DLX1, DLX2, DLX5, among others. Previously it has been reported that DLX6-AS1 regulates the methylation of enhancers by modulating the orchestra of activators such as DLX1/DLX2 and repressor MECP2 39 . Hence in our view, DLX6-AS1 and other lncRNAs potentially governing epigenetic profiling to maintain the architecture of the neocortical regions. ...
Human and non-human primates have strikingly similar genomes, but they strongly differ in many brain-based processes (e.g., behaviour and cognition). While the functions of protein-coding genes have been extensively studied, rather little is known about the role of non-coding RNAs such as long non-coding RNAs (lncRNAs). Here, we predicted lncRNAs and analysed their expression pattern across different brain regions of human and non-human primates (chimpanzee, gorilla, and gibbon). Our analysis identified shared orthologous and non-orthologous lncRNAs, showing striking differences in the genomic features. Differential expression analysis of the shared orthologous lncRNAs from humans and chimpanzees revealed distinct expression patterns in subcortical regions (striatum, hippocampus) and neocortical areas while retaining a homogeneous expression in the cerebellum. Co-expression analysis of lncRNAs and protein-coding genes revealed massive proportions of co-expressed pairs in neocortical regions of humans compared to chimpanzees. Network analysis of co-expressed pairs revealed the distinctive role of the hub-acting orthologous lncRNAs in a region- and species-specific manner. Overall, our study provides novel insight into lncRNA driven gene regulatory landscape, neural regulation, brain evolution, and constitutes a resource for primate’s brain lncRNAs.
... Evf2/Dlx6os1 (distal-less homeobox 6, opposite strand 1) accumulates in a local ''cloud'' encompassing the domain from which it is transcribed. Within this cloud the nearby Dlx5/6 genes are regulated via Evf2-dependent recruitment of Dlx2 and MeCP2 (Berghoff et al., 2013;Bond et al., 2009). Kcnq1ot1 (KCNQ1 opposite strand/antisense transcript 1) is expressed from the imprinted Kcnq1 domain and interacts with histone methyltransferase G9a and PRC2 components Ezh2 and Suz12 in a tissue-specific manner to regulate local chromatin remodeling (Pandey et al., 2008). ...
Long non-coding RNA (lncRNA) function is mediated by the process of transcription or through transcript-dependent associations with proteins or nucleic acids to control gene regulatory networks. Many lncRNAs are transcribed in the ventricular-subventricular zone (V-SVZ), a postnatal neural stem cell niche. lncRNAs in the V-SVZ are implicated in neurodevelopmental disorders, cancer, and brain disease, but their functions are poorly understood. V-SVZ neurogenesis capacity declines with age due to stem cell depletion and resistance to neural stem cell activation. Here we analyzed V-SVZ transcriptomics by pooling current single-cell RNA-seq data. They showed consistent lncRNA expression during stem cell activation, lineage progression, and aging. In conjunction with epigenetic and genetic data, we predicted V-SVZ lncRNAs that regulate stem cell activation and differentiation. Some of the lncRNAs validate known epigenetic mechanisms, but most remain uninvestigated. Our analysis points to several lncRNAs that likely participate in key aspects of V-SVZ stem cell activation and neurogenesis in health and disease.
... The human genome contains 16,193 annotated lncRNAs [8]. They are divided into the following categories based on their protein-coding sequence sites: 1) Sense: The transcripts of these lncRNAs overlap with the exons of other transcripts and are transcribed from RNA-coding sequences. ...
Cardiovascular diseases (CVDs) are a group of disorders with major global health consequences. The prevalence of CVDs continues to grow due to population-aging and lifestyle modifications. Non-coding RNAs (ncRNAs) as key regulators of cell signaling pathways have gained attention in the occurrence and development of CVDs. Exosomal-lncRNAs (exos-lncRNAs) are emerging biomarkers due to their high sensitivity and specificity, stability, accuracy and accessibility in the biological fluids. Recently, circulatory and exos-based-lncRNAs are emerging and novel bio-tools in various pathogenic conditions. It is worth mentioning that dysregulation of these molecules has been found in different types of CVDs. In this regard, we aimed to discuss the knowledge gaps and suggest research priorities regarding circulatory and exos-lncRNAs as novel bio-tools and therapeutic targets for CVDs.
... It also interacts with methyl-CpG binding protein 2 (MECP2) targeting it to the Dlx gene transcriptional control region where MECP2 acts as a transcriptional repressor (Bond et al, 2009). MECP2 acts in a regulatory loop inhibiting the expression of Evf2 by antagonising its transcriptional activator Dlx2 (Berghoff et al, 2013). The regulatory role of Evf2 lncRNA is essential for the correct development of GABAergic interneurons (i.e. ...
In this thesis I describe my PhD work on the long non-coding RNA maternally expressed gene 3 (MEG3). The main aim of my project was to understand the molecular mechanism of MEG3 in regulating p53-dependent gene expression. I describe the characterisation of MEG3 at the structural, functional and evolutionary levels. Through detailed experimental analysis of the secondary structure of three human MEG3 splicing isoforms, characterisation of common tertiary structural elements and use of a systematic in cellulo functional luciferase reporter assay, I contributed to establishing a structure-to-function axis for the mechanism of MEG3 function. Furthermore, I studied the evolution of MEG3 in mammals and I provide theoretical evidence for the conservation of a functional mechanism of MEG3 relying on its structural features. In addition, I provide experimental data exploring the conservation of MEG3 structure and function from humans to mice and juxtapose the similarities and differences between the two lncRNA homologues. In summary, my work helped to reveal that, MEG3 is organised in distinct domains and that its relative domain organisation depends on exon composition both in humans and mice. However, the exact active motifs driving MEG3 function in humans and mice differ. Finally, I propose a mechanism of action for MEG3-driven p53-dependent gene expression in humans. According to this mechanism, MEG3 exon composition dictates its secondary folding which in turn affects its long-range interactions and tertiary fold into a globular-like structure. Subsequently, MEG3 tertiary fold allows the correct MEG3-protein interactions to form regulating its action on gene expression regulation.
A complex sequence of occurrences, including host genetic vulnerability, Helicobacter pylori infection, and other environmental variables, culminate in gastric cancer (GC). The development of several genetic and epigenetic changes in oncogenes and tumor suppressor genes causes dysregulation of several signaling pathways, which upsets the cell cycle and the equilibrium between cell division and apoptosis, leading to GC. Developments in computational biology and RNA-seq technology enable quick detection and characterization of long non-coding RNAs (lncRNAs). Recent studies have shown that long non-coding RNAs (lncRNAs) have multiple roles in the development of gastric cancer. These lncRNAs interact with molecules of protein, RNA, DNA, and/or combinations. This review article explores several gastric cancer-associated lncRNAs, such as ADAMTS9-AS2, UCA1, XBP-1, and LINC00152. These various lncRNAs could change GC cell apoptosis, migration, and invasion features in the tumor microenvironment. This review provides an overview of the most recent research on lncRNAs and GC cell apoptosis, migration, invasion, and drug resistance, focusing on studies conducted in cancer cells and healthy cells during differentiation.
Understanding how genes are selectively regulated during development is a major goal in biology. While DNA enhancers selectively regulate genes at a distance, mechanisms regulating long distance enhancer interactions are only beginning to be understood. Our previous work reported transcriptional activity by Evf2 , an enhancer long non‐coding RNA (lncRNA) transcribed from the Dlx5/6 ultraconserved enhancer ( Dlx5/6ei )1. Evf2 regulates adjacent chr6 genes Dlx5/6, recruiting both activators and repressors to Dlx5/6ei, and forms a large ribonucleoprotein complex ( Evf2 ‐RNP, ~79 proteins) that contains the DLX1 homeodomain transcription factor and chromatin remodelers2,3,4. Promiscuous interactions between Evf2 and chromatin remodelers reveal RNA‐mediated direct inhibition of BRG1(SMARCA4) ATPase and remodeling activities4. Thus, enhancer RNAs can regulate enhancer activity by providing a scaffold for multiple promiscuous RNA binding proteins, and directly regulating enzymatic activity. Here, we show evidence supporting that Evf2 controls chromosome‐wide enhancer interactions and histone modifications, selectively regulating genes located in a ~27Mb region of chr6 ( Evf2 ‐ chr6 targets). These data support the idea and that while Evf2 plays a major role in chromosome topology, only a subset of Evf2 ‐dependent enhancer interactions contribute to gene regulation. Evf2 loss, truncation, and rescue distinguish between the roles of the Evf2‐5 ′ ultraconserved enhancer‐containing region and trans/cis mechanisms that regulate Evf2‐chr6 targets. Together, this work identifies a novel network of interneuron subtype gene regulation that links enhancer lncRNA directed chromosomal interactions and interneuron diversity in the embryonic mouse brain.
Support or Funding Information
NIMH R01MH094653 to J.D.K
Long non-coding RNAs (lncRNAs) has become a vital regulator in the pathogenesis of osteoporosis (OP). This study aimed to investigate the role of lncRNA DLEU2 in the development of proliferation and apoptosis of human bone marrow mesenchymal stem cells (hBMSCs). High-throughput sequencing in bone tissues from 3 pairs of healthy donors and OP patients was used to search for differential lncRNAs. The expression of DLEU2 was also verified in bone tissues. The hBMSCs were transfected with DLEU2 ASO. Cell viability was detected suing MTT. Cell proliferation was determined using colony formation and EdU assays. Cell cycle and apoptosis was detected using flow cytometry. RIP, RNA pulldown, and Co-IP assays were carried out to verify the interaction between protein and protein/RNA. The binding sites between GFI1 and the promoter of DLEU2 was verified using ChIP and luciferase assays. DLEU2 expression was down-regulated in OP patients. Knockdown of DLEU2 expression significantly inhibited proliferation and promoted apoptosis of hBMSCs. Moreover, DLEU2 could interact with EZH2 to induce the activation of GFI1. Additionally, GFI1 transcriptionally activated DLEU2. Taken together, DLEU2/EZH2/GFI1 axis suppressed proliferation and enhanced hBMSC apoptosis. This may provide novel strategy for OP.
DNA methylation is one of the most important epigenetic mechanisms that governing regulation of gene expression, aberrant DNA methylation patterns are strongly associated with human malignancies. Long non-coding RNAs (lncRNAs) have being discovered as a significant regulator on gene expression at the epigenetic level. Emerging evidences have indicated the intricate regulatory effects between lncRNAs and DNA methylation. On one hand, transcription of lncRNAs are controlled by the promoter methylation, which is similar to protein coding genes, on the other hand, lncRNA could interact with enzymes involved in DNA methylation to affect the methylation pattern of downstream genes, thus regulating their expression. In addition, circular RNAs (circRNAs) being an important class of noncoding RNA are also found to participate in this complex regulatory network. In this review, we summarize recent research progress on this crosstalk between lncRNA, circRNA, and DNA methylation as well as their potential functions in complex diseases including cancer. This work reveals a hidden layer for gene transcriptional regulation and enhances our understanding for epigenetics regarding detailed mechanisms on lncRNA regulatory function in human cancers.
Many long noncoding RNA (lncRNA) species have been identified in mammalian cells, but the genomic origin and regulation of these molecules in individual cell types is poorly understood. We have generated catalogs of lncRNA species expressed in human and murine embryonic stem cells and mapped their genomic origin. A surprisingly large fraction of these transcripts (>60%) originate from divergent transcription at promoters of active protein-coding genes. The divergently transcribed lncRNA/mRNA gene pairs exhibit coordinated changes in transcription when embryonic stem cells are differentiated into endoderm. Our results reveal that transcription of most lncRNA genes is coordinated with transcription of protein-coding genes.
Dlx homeobox genes play a crucial role in the migration and differentiation of the subpallial precursor cells that give rise to various subtypes of gamma-aminobutyric acid (GABA)-expressing neurons of the forebrain, including local-circuit cortical interneurons. Aberrant development of GABAergic interneurons has been linked to several neurodevelopmental disorders, including epilepsy, schizophrenia, Rett syndrome and autism. Here, we report in mice that a single-nucleotide polymorphism (SNP) found in an autistic proband falls within a functional protein binding site in an ultraconserved cis-regulatory element. This element, I56i, is involved in regulating Dlx5/Dlx6 homeobox gene expression in the developing forebrain. We show that the SNP results in reduced I56i activity, predominantly in the medial and caudal ganglionic eminences and in streams of neurons tangentially migrating to the cortex. Reduced activity is also observed in GABAergic interneurons of the adult somatosensory cortex. The SNP affects the affinity of Dlx proteins for their binding site in vitro and reduces the transcriptional activation of the enhancer by Dlx proteins. Affinity purification using I56i sequences led to the identification of a novel regulator of Dlx gene expression, general transcription factor 2 I (Gtf2i), which is among the genes most often deleted in Williams-Beuren syndrome, a neurodevelopmental disorder. This study illustrates the clear functional consequences of a single nucleotide variation in an ultraconserved non-coding sequence in the context of developmental abnormalities associated with disease.
A long noncoding RNA, Kcnq1ot1, regulates the expression of both ubiquitously and tissue-specific imprinted genes within the Kcnq1 domain. However, the functional sequences of the Kcnq1ot1 RNA that mediate lineage-specific imprinting are unknown. Here, we have generated a knockout mouse with a deletion encompassing an 890-bp silencing domain (Delta890) downstream of the Kcnq1ot1 promoter. Maternal transmission of the Delta890 allele has no effect on imprinting, whereas paternal inheritance of the deletion leads to selective relaxation of the imprinting of ubiquitously imprinted genes to a variable extent in a tissue-specific manner. Interestingly, the deletion affects DNA methylation at somatically acquired differentially methylated regions (DMRs), but does not affect the histone modifications of the ubiquitously imprinted genes. Importantly, we found that Kcnq1ot1 recruits Dnmt1 to somatic DMRs by interacting with Dnmt1, and that this interaction was significantly reduced in the Delta890 mice. Thus, the ubiquitous and placental-specific imprinting of genes within the Kcnq1 domain might be mediated by distinct mechanisms, and Kcnq1ot1 RNA might mediate the silencing of ubiquitously imprinted genes by maintaining allele-specific methylation through its interactions with Dnmt1.
Genomic studies demonstrate that, although the majority of the mammalian genome is transcribed, only about 2% of these transcripts are code for proteins. We investigated how the long, polyadenylated Evf2 noncoding RNA regulates transcription of the homeodomain transcription factors DLX5 and DLX6 in the developing mouse forebrain. We found that, in developing ventral forebrain, Evf2 recruited DLX and MECP2 transcription factors to important DNA regulatory elements in the Dlx5/6 intergenic region and controlled Dlx5, Dlx6 and Gad1 expression through trans and cis-acting mechanisms. Evf2 mouse mutants had reduced numbers of GABAergic interneurons in early postnatal hippocampus and dentate gyrus. Although the numbers of GABAergic interneurons and Gad1 RNA levels returned to normal in Evf2 mutant adult hippocampus, reduced synaptic inhibition occurred. These results suggest that noncoding RNA-dependent balanced gene regulation in embryonic brain is critical for proper formation of GABA-dependent neuronal circuitry in adult brain.
Distal-less is the earliest known gene specifically expressed in developing insect limbs; its expression is maintained throughout limb development. The homeodomain transcription factor encoded by Distal-less is required for the elaboration of proximodistal pattern elements in Drosophila limbs and can initiate proximodistal axis formation when expressed ectopically. Distal-less homologs, the Dlx genes, are expressed in developing appendages in at least six phyla, including chordates, consistent with requirements for Dlx function in normal appendage development across the animal kingdom. Recent work implicates the Dlx genes of vertebrates in a variety of other developmental processes ranging from neurogenesis to hematopoiesis. We review what is known about the invertebrate and vertebrate Dll/Dlx genes and their varied roles during development. We propose revising the vertebrate nomenclature to reflect phylogenetic relationships among the Dlx genes.
X chromosome inactivation and genomic imprinting are classic epigenetic processes that cause disease when not appropriately regulated in mammals. Whereas X chromosome inactivation evolved to solve the problem of gene dosage, the purpose of genomic imprinting remains controversial. Nevertheless, the two phenomena are united by allelic control of large gene clusters, such that only one copy of a gene is expressed in every cell. Allelic regulation poses significant challenges because it requires coordinated long-range control in cis and stable propagation over time. Long noncoding RNAs have emerged as a common theme, and their contributions to diseases of imprinting and the X chromosome have become apparent. Here, we review recent advances in basic biology, the connections to disease, and preview potential therapeutic strategies for future development.
DNA methylation is among the best studied epigenetic modifications and is essential to mammalian development. Although the methylation status of most CpG dinucleotides in the genome is stably propagated through mitosis, improvements to methods for measuring methylation have identified numerous regions in which it is dynamically regulated. In this Review, we discuss key concepts in the function of DNA methylation in mammals, stemming from more than two decades of research, including many recent studies that have elucidated when and where DNA methylation has a regulatory role in the genome. We include insights from early development, embryonic stem cells and adult lineages, particularly haematopoiesis, to highlight the general features of this modification as it participates in both global and localized epigenetic regulation.
Recent studies show that transcription of the mammalian genome is not only pervasive but also enormously complex. It is estimated
that an average of 10 transcription units, the vast majority of which make long noncoding RNAs (lncRNAs), may overlap each
traditional coding gene. These lncRNAs include not only antisense, intronic, and intergenic transcripts but also pseudogenes
and retrotransposons. Do they universally have function, or are they merely transcriptional by-products of conventional coding
genes? A glimpse into the molecular biology of multiple emerging lncRNA systems reveals the “Wild West” landscape of their
functions and mechanisms and the key problems to solve in the years ahead toward understanding these intriguing macromolecules.
Genomic imprinting is an epigenetic process leading to parental-specific expression of one to two percent of mammalian genes that offers one of the best model systems for a molecular analysis of epigenetic regulation in development and disease. In the twenty years since the first imprinted gene was identified, this model has had a significant impact on decoding epigenetic information in mammals. So far it has led to the discovery of long-range cis-acting control elements whose epigenetic state regulates small clusters of genes and of unusual macro noncoding RNAs (ncRNAs) that directly repress genes in cis, and critically, it has demonstrated that one biological role of DNA methylation is to allow expression of genes normally repressed by default. This review describes the progress in understanding how imprinted protein-coding genes are silenced; in particular, it focuses on the role of macro ncRNAs that have broad relevance as a potential new layer of regulatory information in the mammalian genome.
Epigenetic modifications of the genome are generally stable in somatic cells of multicellular organisms. In germ cells and early embryos, however, epigenetic reprogramming occurs on a genome-wide scale, which includes demethylation of DNA and remodeling of histones and their modifications. The mechanisms of genome-wide erasure of DNA methylation, which involve modifications to 5-methylcytosine and DNA repair, are being unraveled. Epigenetic reprogramming has important roles in imprinting, the natural as well as experimental acquisition of totipotency and pluripotency, control of transposons, and epigenetic inheritance across generations. Small RNAs and the inheritance of histone marks may also contribute to epigenetic inheritance and reprogramming. Reprogramming occurs in flowering plants and in mammals, and the similarities and differences illuminate developmental and reproductive strategies.