Figure 1
Bivalent domains underlie epigenetic switches in stem cells. At bivalent domains the simultaneous presence of repressive (red hexagon) and active (green hexagon) chromatin marks counterbalance each other. Polycomb complexes (PcG, comprising PRC1 and PRC2) confer repression by H3K27me3 catalyzed by the subunit Suz12. Ten − eleven translocation proteins (Tet) interact with bivalent domains and catalyze DNA demethylation. Activating transcription factors (TF) together with histone H3K27 demethylases (SET1 and MLL) and H2. A-deubiqitinating enzymes (DUBs) tilt the balance towards activation and replacement of repressive protein complexes. Conversely, loss of activating protein complexes switches bivalent domains into a repressed state by recruitment of H3K4 demethylase (KDM5). Histone methyltransferases (HMT) mediated H3K9 methylation and de novo DNA methyltransferase (DNMT3) mediated DNA methylation lock in repression.
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Epigenetic mechanisms encode information above and beyond DNA sequence and play a critical role in brain development and the long-lived effects of environmental cues on the pre- and postnatal brain. Switch-like, rather than graded changes, illustrate par excellence how epigenetic events perpetuate altered activity states in the absence of the initi...
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Context 1
... subset of trxG proteins-comprising SET1A, SET1B, and mix lineage leukemia (MLL) proteins 1-4 in mammals (Shilatifard, 2012) catalyze trimethylation of histone H3Lys-4 (H3K4me3), an activating mark. In contrast, PcG proteins confer silencing by formation of the Polycomb-repressive complexes (PRCs) 1 and 2, whereby the enzymatic subunit of PRC2, the histone methyltransferase Suz12, catalyzes H3K27me3, a hallmark of repressive chromatin (Simon and Kingston, 2013; Figure 1). ...
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... neuronal differentiation, some bivalent genes underwent expression concomitant with the departure of H3K27me3, while others undergoing silencing lost H3K4me3 but retained H3K27me3. These findings inspired the intriguing hypothesis that bivalent domains serve to keep developmental genes on standby primed for subsequent expression and to defend against unscheduled expression (Figure 1). Collectively, bivalent domains are thought to reduce transcriptional noise in favor of robust developmental decisions ( Bernstein et al., 2006). ...
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... this dynamic equilibrium between activation and repression is tilted towards differentiation, switch-like, robust ''ON or OFF'' decisions, rather than graded responses, take place. As a result bivalent domains give way to gene silencing or expression in a cell-lineage and/or cell-type specific fashion (Figure 1). ...
Citations
... Gene set enrichment analysis (GSEA) was applied to underexpressed genes and identified many enriched gene sets, of which the most significantly enriched was 'ZHAN_MULTIPLE_MYELOMA_MS_UP,' representing genes that were upregulated in a subtype of multiple myeloma that is defined by overexpression of NSD2 (also known as WHSC1) (40) (Supplementary Material, Table S6). This indicates overlap between genes that are positively regulated by NSD1 and its paralogue NSD2, presumably due to their shared H3K36me1/2 methyltransferase activity (41,42). ...
... Aberrant silencing of bivalent genes could account for neurodevelopmental phenotypes of SS, since neurodevelopmental genes often feature bivalent promoters (42). Moreover, underexpressed genes included a strong enrichment of synaptic membrane-expressed genes. ...
Sotos syndrome (SS), the most common overgrowth with intellectual disability (OGID) disorder, is caused by inactivating germline mutations of NSD1, which encodes a histone H3 lysine 36 methyltransferase. To understand how NSD1 inactivation deregulates transcription and DNA methylation (DNAm), and to explore how these abnormalities affect human development, we profiled transcription and DNAm in SS patients and healthy control individuals. We identified a transcriptional signature that distinguishes individuals with SS from controls and was also deregulated in NSD1 mutated cancers. Most abnormally expressed genes displayed reduced expression in SS; these downregulated genes consisted mostly of bivalent genes and were enriched for regulators of development and neural synapse function. DNA hypomethylation was strongly enriched within promoters of transcriptionally deregulated genes: Overexpressed genes displayed hypomethylation at their transcription start sites (TSSs) while underexpressed genes featured hypomethylation at polycomb binding sites within their promoter CpG island shores. SS patients featured accelerated molecular aging at the levels of both transcription and DNAm. Overall, these findings indicate that NSD1-deposited H3K36 methylation regulates transcription by directing promoter DNA methylation, partially by repressing polycomb repressive complex 2 (PRC2) activity. These findings could explain the phenotypic similarity of SS to OGID disorders that are caused by mutations in PRC2 complex-encoding genes.
... Interestingly, almost one third of anti-CCP2-negative RA patients are anti-b-Raf-(serine/threonine-protein kinase b-Raf) positive [2,57]. So, these are one of the most interesting auto-antibodies for classifying ACPA-negative RA patients [58]. Moreover, Abs to the heterogeneous nuclear ribonucleoprotein A2/B1 (Anti-RA33) and T-cells targeting RA33 can also be associated with the autoimmunity and inflammation [59]. ...
... Epigenetic mechanisms are sensitive to external stimuli, and epigenetic alterations are crucial for the development of immune cells and the modulation of their differentiation processes. These processes are highly pivotal in antibody maturation and the auto-antibody response [58,61]. Once selected for proliferation and survival, B-cells differentiate into either plasma or memory cells depending on different stimuli to which they are exposed. ...
Rheumatoid arthritis (RA) is considered a chronic systemic, multi-factorial, inflammatory, and progressive autoimmune disease affecting many people worldwide. While patients show very individual courses of disease, with RA focusing on the musculoskeletal system, joints are often severely affected, leading to local inflammation, cartilage destruction, and bone erosion. To prevent joint damage and physical disability as one of many symptoms of RA, early diagnosis is critical. Auto-antibodies play a pivotal clinical role in patients with systemic RA. As biomarkers, they could help to make a more efficient diagnosis, prognosis, and treatment decision. Besides auto-antibodies, several other factors are involved in the progression of RA, such as epigenetic alterations, post-translational modifications, glycosylation, autophagy, and T-cells. Understanding the interplay between these factors would contribute to a deeper insight into the causes, mechanisms, progression, and treatment of the disease. In this review, the latest RA research findings are discussed to better understand the pathogenesis, and finally, treatment strategies for RA therapy are presented, including both conventional approaches and new methods that have been developed in recent years or are currently under investigation.
... The presence of molecular epigenetic switches allows a dynamic regulation, capable of changing gene expression quickly and efficiently to face different environmental and developmental states. The existence of bivalent chromatin domains provides persuasive evidence of molecular epigenetic switches that regulate gene expression (Hoffmann et al., 2015). The bivalent domains produced by TrxG and PcG serve to keep developmental genes on standby, primed for subsequent expression and to protect against unscheduled expression, reducing transcriptional noise in favor of robust developmental decisions (Hoffmann et al., 2015). ...
... The existence of bivalent chromatin domains provides persuasive evidence of molecular epigenetic switches that regulate gene expression (Hoffmann et al., 2015). The bivalent domains produced by TrxG and PcG serve to keep developmental genes on standby, primed for subsequent expression and to protect against unscheduled expression, reducing transcriptional noise in favor of robust developmental decisions (Hoffmann et al., 2015). Although in plant biological studies, bivalent marks in the same locus have been little addressed and still remain elusive, finding proteins involved in both activation and repression processes shows the relevance of bivalent marks to regulating gene expression quickly and efficiently. ...
ULTRAPETALA1 (ULT1) is a versatile plant-exclusive protein, initially described as a trithorax group (TrxG) factor that regulates transcriptional activation and counteracts polycomb group (PcG) repressor function. As part of TrxG, ULT1 interacts with ARABIDOPSIS TRITHORAX1 (ATX1) to regulate H3K4me3 activation mark deposition. However, our recent studies indicate that ULT1 can also act independently of ATX1. Moreover, the ULT1 ability to interact with transcription factors (TFs) and PcG proteins indicates that it is a versatile protein with other roles. Therefore, in this work we revised recent information about the function of Arabidopsis ULT1 to understand the roles of ULT1 in plant development. Furthermore, we discuss the molecular mechanisms of ULT1, highlighting its epigenetic role, in which ULT1 seems to have characteristics of an epigenetic molecular switch that regulates repression and activation processes via TrxG and PcG complexes.
... This result is in agreement with a number of independent studies on the role of CHD8 and other CHD proteins in cell cycle regulation [45][46][47][48]. Interestingly, Chd8-deficient NPCs showed additionally deregulation of numerous known ASD risk genes, and of genes controlled by Wnt signaling and the Polycomb group (PcG) repressive complex (the role of PcG for neurodevelopment is reviewed in [49,50]). These findings led the authors to propose that Chd8 promoted NPC self-renewal by transactivation of cell cycle genes and PcG-mediated downregulation of neural genes. ...
Chromodomain Helicase DNA-binding 8 (CHD8) is a high confidence risk factor for autism spectrum disorders (ASDs) and the genetic cause of a distinct neurodevelopmental syndrome with the core symptoms of autism, macrocephaly, and facial dysmorphism. The role of CHD8 is well-characterized at the structural, biochemical, and transcriptional level. By contrast, much less is understood regarding how mutations in CHD8 underpin altered brain function and mental disease. Studies on various model organisms have been proven critical to tackle this challenge. Here, we scrutinize recent advances in this field with a focus on phenotypes in transgenic animal models and highlight key findings on neurodevelopment, neuronal connectivity, neurotransmission, synaptic and homeostatic plasticity, and habituation. Against this backdrop, we further discuss how to improve future animal studies, both in terms of technical issues and with respect to the sex-specific effects of Chd8 mutations for neuronal and higher-systems level function. We also consider outstanding questions in the field including ‘humanized’ mice models, therapeutic interventions, and how the use of pluripotent stem cell-derived cerebral organoids might help to address differences in neurodevelopment trajectories between model organisms and humans.
... CpG methylation is performed by DNA methyl transferases (DNMT's). This family of enzymes include DNMT1 that preserves DNA methylation during development (Hoffmann et al., 2015), DNMT3A and DNMT3B that perform de novo DNA methylation (Hoffmann et al., 2015). Recently, hydroxymethylation, leading to active CpG demethylation by the ten-eleven translocation (TET) family enzymes, was discovered (Kohli and Zhang, 2013). ...
... CpG methylation is performed by DNA methyl transferases (DNMT's). This family of enzymes include DNMT1 that preserves DNA methylation during development (Hoffmann et al., 2015), DNMT3A and DNMT3B that perform de novo DNA methylation (Hoffmann et al., 2015). Recently, hydroxymethylation, leading to active CpG demethylation by the ten-eleven translocation (TET) family enzymes, was discovered (Kohli and Zhang, 2013). ...
Early life encounters with stress can lead to long-lasting beneficial alterations in the response to various stressors, known as cross-tolerance. Embryonic heat conditioning (EHC) of chicks was previously shown to mediate resilience to heat stress later in life. Here we demonstrate that EHC can induce cross-tolerance with the immune system, attenuating hypothalamic inflammation. Inflammation in EHC chicks was manifested, following lipopolysaccharide (LPS) challenge on day 10 post-hatch, by reduced febrile response and reduced expression of LITAF and NFκB compared to controls, as well as nuclear localization and activation of NFκB in the hypothalamus. Since the cross-tolerance effect was long-lasting, we assumed that epigenetic mechanisms are involved. We focused on the role of ten-eleven translocation (TET) family enzymes, which are the mediators of active CpG demethylation. Here, TET transcription during early life stress was found to be necessary for stress resilience later in life. The expression of the TET family enzymes in the midbrain during conditioning increased in parallel to an elevation in concentration of their cofactor α-ketoglutarate. In-ovo inhibition of TET activity during EHC, by the α-ketoglutarate inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES), resulted in reduced total and locus specific CpG demethylation in 10-day-old chicks and reversed both thermal and inflammatory resilience. In addition, EHC attenuated the elevation in expression of the stress markers HSP70, CRHR1, and CRHR2, during heat challenge on day 10 post-hatch. This reduction in expression was reversed by BPTES. Similarly, the EHC-dependent reduction of inflammatory gene expression during LPS challenge was eliminated in BPTES-treated chicks. Thus, TET family enzymes and CpG demethylation are essential for the embryonic induction of stress cross-tolerance in the hypothalamus.
... While in embryonic stem cells and embryo bivalency is postulated to poise developmentally crucial genes for later activation during differentiation, de novo acquired tissue-restricted bivalency results in repression of affected genes in intestine and expression of these genes in the brain [16,17]. Currently, bivalency is thought to play a vital role in development [19], face morphogenesis [20], female puberty [21], phenotypic differences between species [18] and genetic diversity in neurons [22,23]. Despite its apparent importance, bivalency is functionally and mechanistically not well understood. ...
Polycomb group (PcG) and Trithorax group (TrxG) proteins orchestrate development of a multicellular organism by faithfully maintaining cell fate decisions made early in embryogenesis. An important chromatin mark connected to PcG/TrxG regulation are bivalent domains, the simultaneous presence of H3K27me3 and H3K4me3 on a given locus, originally identified in mammalian embryonic stem cells but considered to be absent in invertebrates. Here, we provide evidence for existence of bivalency in fly embryos. Using a recently described PcG reporter fly line, we observed a strong reporter inducibility in embryo and its sharp decrease in larval and adult stages. Analysis of the chromatin landscape of the reporter revealed a strong signal for the repressive PcG mark, H3K27me3, in all three developmental stages and, surprisingly, a strong signal for a transcriptionally activating H3K4me3 mark in embryo. Using re-ChIP experiments, bivalent domains were also uncovered at endogenous PcG targets like the Hox genes.
... Notably, in pluripotent and multipotent cells such as embryonic stem (ES) and neuroprogenitor cells (NPCs), critical regulatory genes may display both H3K4 and H3K27 trimethylation, a chromatin signature referred to as 'bivalent domains' that are poised for rapid activation or, diversely, silencing. Such events may shift a balance in expression of oncogenes and tumor suppressors, and lead to malignant transformation and tumorigenesis [30]. A major factor in this regulation PRC2 has histone methyltransferase activity and silences gene expression by dimethylating or trimethylating H3K27. ...
Malignant brain tumors are rapidly progressive and often fatal owing to resistance to therapies and based on their complex biology, heterogeneity, and isolation from systemic circulation. Glioblastoma is the most common and most aggressive primary brain tumor, has high mortality, and affects both children and adults. Despite significant advances in understanding the pathology, multiple clinical trials employing various treatment strategies have failed. With much expanded knowledge of the GBM genome, epigenome, and transcriptome, the field of neuro-oncology is getting closer to achieve breakthrough-targeted molecular therapies. Current developments of oligonucleotide chemistries for CNS applications make this new class of drugs very attractive for targeting molecular pathways dysregulated in brain tumors and are anticipated to vastly expand the spectrum of currently targetable molecules. In this chapter, we will overview the molecular landscape of malignant gliomas and explore the most prominent molecular targets (mRNAs, miRNAs, lncRNAs, and genomic mutations) that provide opportunities for the development of oligonucleotide therapeutics for this class of neurologic diseases. Because malignant brain tumors focally disrupt the blood–brain barrier, this class of diseases might be also more susceptible to systemic treatments with oligonucleotides than other neurologic disorders and, thus, present an entry point for the oligonucleotide therapeutics to the CNS. Nevertheless, delivery of oligonucleotides remains a crucial part of the treatment strategy. Finally, synthetic gRNAs guiding CRISPR–Cas9 editing technologies have a tremendous potential to further expand the applications of oligonucleotide therapeutics and take them beyond RNA targeting.
... Epigenetic mechanisms, i.e. the enzymatic regulation of transcription activity and gene expression without altering DNA sequence via acetylation, methylation, ubiquitination, phosphorylation and sumoylation on histones, DNA or via microRNA-mediated regulation of translation plays a pivotal role in normal and disturbed brain development and may be associated with neurodevelopmental and/or neuropsychiatric diseases later in life [183][184][185] . Interestingly, perinatal brain injury either induced by inflammatory triggers or by stress has been linked to sustained epigenetic alterations associated with adverse neurodevelopmental outcome 18,150 . ...
Perinatal brain injury is a leading cause of death and disability in young children. Recent advances in obstetrics, reproductive medicine and neonatal intensive care have resulted in significantly higher survival rates of preterm or sick born neonates, at the price of increased prevalence of neurological, behavioural and psychiatric problems in later life. Therefore, the current focus of experimental research shifts from immediate injury processes to the consequences for brain function in later life. The aetiology of perinatal brain injury is multi-factorial involving maternal and also labour-associated factors, including not only placental insufficiency and hypoxia–ischaemia but also exposure to high oxygen concentrations, maternal infection yielding excess inflammation, genetic factors and stress as important players, all of them associated with adverse long-term neurological outcome. Several animal models addressing these noxious stimuli have been established in the past to unravel the underlying molecular and cellular mechanisms of altered brain development. In spite of substantial efforts to investigate short-term consequences, preclinical evaluation of the long-term sequelae for the development of cognitive and neuropsychiatric disorders have rarely been addressed. This review will summarise and discuss not only current evidence but also requirements for experimental research providing a causal link between insults to the developing brain and long-lasting neurodevelopmental disorders.
... In addition to this rigid role, recent findings show that PcG proteins are also involved in the dynamic and recurrent "On-Off" switches in gene regulatory activity [11] that contribute to distinct cell lineage decisions and the nascence of highly diverse cell types [10,[12][13][14]. These regulatory transitions are guided by molecular epigenetic mechanisms that elsewise sustain a memory of cellular identity throughout development [3,15,16]. ...
... This review article will focus on the regulation of DNA methylation and two types of histone modification: methylation and acetylation and their relevance to stem cell fate decisions in neurodevelopmental processes. The epigenetic events are considered to act in a switch-like mode (Hoffmann et al., 2015), however the potential of the cell to undertake developmental decisions, stemness/lineage commitment and further differentiation is highly dependent on the activity of the genes typical for the defined stage of development. A schematic correlation of neurodevelopmental hierarchy of stem cells, along with their epigenetic status is presented on Figure 1. ...
The coordinated development of the nervous system requires fidelity in the expression of specific genes determining the different neural cell phenotypes. Stem cell fate decisions during neurodevelopment are strictly correlated with their epigenetic status. The epigenetic regulatory processes, such as DNA methylation and histone modifications discussed in this review article, may impact both neural stem cell (NSC) self-renewal and differentiation and thus play an important role in neurodevelopment. At the same time, stem cell decisions regarding fate commitment and differentiation are highly dependent on the temporospatial expression of specific genes contingent on the developmental stage of the nervous system. An interplay between the above, as well as basic cell processes, such as transcription regulation, DNA replication, cell cycle regulation and DNA repair therefore determine the accuracy and function of neuronal connections. This may significantly impact embryonic health and development as well as cognitive processes such as neuroplasticity and memory formation later in the adult.
