http://www.epigeneticsandchromatin.com The most accessed research articles published by Epigenetics & Chromatin 2012-01-30T00:00:00Z Regulatory DNA elements like enhancers, silencers, and insulators are embedded in metazoan genomes, and they control gene expression during development. Although they fulfil different roles, they share specific properties. Some examples are discussed, and a parsimonious model for their function proposed; all are transcription units that tether their target promoters close to, or distant from, transcriptional hot-spots (or 'factories'). http://www.epigeneticsandchromatin.com/content/5/1/1 Petros Kolovos Tobias Knoch Frank Grosveld Peter Cook Argyris Papantonis Epigenetics & Chromatin 2012, null:1 2012-01-09T00:00:00Z doi:10.1186/1756-8935-5-1 /content/figures/1756-8935-5-1-toc.gif Epigenetics & Chromatin 1756-8935 ${item.volume} 1 2012-01-09T00:00:00Z PDF The integrity of DNA is continuously challenged by metabolism-derived and environmental genotoxic agents that cause a variety of DNA lesions, including base alterations and breaks. DNA damage interferes with vital processes such as transcription and replication, and if not repaired properly, can ultimately lead to premature aging and cancer. Multiple DNA pathways signaling for DNA repair and DNA damage collectively safeguard the integrity of DNA. Chromatin plays a pivotal role in regulating DNA-associated processes, and is itself subject to regulation by the DNA-damage response. Chromatin influences access to DNA, and often serves as a docking or signaling site for repair and signaling proteins. Its structure can be adapted by post-translational histone modifications and nucleosome remodeling, catalyzed by the activity of ATP-dependent chromatin-remodeling complexes. In recent years, accumulating evidence has suggested that ATP-dependent chromatin-remodeling complexes play important, although poorly characterized, roles in facilitating the effectiveness of the DNA-damage response. In this review, we summarize the current knowledge on the involvement of ATP-dependent chromatin remodeling in three major DNA repair pathways: nucleotide excision repair, homologous recombination, and non-homologous end-joining. This shows that a surprisingly large number of different remodeling complexes display pleiotropic functions during different stages of the DNA-damage response. Moreover, several complexes seem to have multiple functions, and are implicated in various mechanistically distinct repair pathways. http://www.epigeneticsandchromatin.com/content/5/1/4 Hannes Lans Jurgen Marteijn Wim Vermeulen Epigenetics & Chromatin 2012, null:4 2012-01-30T00:00:00Z doi:10.1186/1756-8935-5-4 /content/figures/1756-8935-5-4-toc.gif Epigenetics & Chromatin 1756-8935 ${item.volume} 4 2012-01-30T00:00:00Z PDF Background: DNA methylation, histone modifications and nucleosome occupancy act in concert for regulation of gene expression patterns in mammalian cells. Recently, G9a, a H3K9 methyltransferase, has been shown to play a role in establishment of DNA methylation at embryonic gene targets in ES cells through recruitment of de novo DNMT3A/3B enzymes. However, whether G9a plays a similar role in maintenance of DNA methylation in somatic cells is still unclear. Results: Here we show that G9a is not essential for maintenance of DNA methylation in somatic cells. Knockdown of G9a has no measurable effect on DNA methylation levels at G9a-target loci. DNMT3A/3B remain stably anchored to nucleosomes containing methylated DNA even in the absence of G9a, ensuring faithful propagation of methylated states in cooperation with DNMT1 through somatic divisions. Moreover, G9a also associates with nucleosomes in a DNMT3A/3B and DNA methylation-independent manner. However, G9a knockdown synergizes with pharmacologic inhibition of DNMTs resulting in increased hypomethylation and inhibition of cell proliferation. Conclusions: Taken together, these data suggest that G9a is not involved in maintenance of DNA methylation in somatic cells but might play a role in re-initiation of de novo methylation after treatment with hypomethylating drugs, thus serving as a potential target for combinatorial treatments strategies involving DNMTs inhibitors. http://www.epigeneticsandchromatin.com/content/5/1/3 Shikhar Sharma Daniel Gerke Han Han Shinwu Jeong Michael Stallcup Peter Jones Gangning Liang Epigenetics & Chromatin 2012, null:3 2012-01-27T00:00:00Z doi:10.1186/1756-8935-5-3 /content/figures/1756-8935-5-3-toc.gif Epigenetics & Chromatin 1756-8935 ${item.volume} 3 2012-01-27T00:00:00Z PDF Background: The tumor suppressor menin (MEN1) is mutated in the inherited disease multiple endocrine neoplasia type I, and has several documented cellular roles, including the activation and repression of transcription effected by several transcription factors. As an activator, MEN1 is a component of the Set1-like mixed lineage leukemia (MLL) MLL1/MLL2 methyltransferase complex that methylates histone H3 lysine 4 (H3K4). MEN1 is localized to the signal transducer and activator of transcription 1 (STAT1)-dependent gene, interferon regulatory factor 1 (IRF1), and is further recruited when IRF1 transcription is triggered by interferon-γ signaling. Results: RNAi-mediated knockdown of MEN1 alters the H3K4 dimethylation and H3 acetylation profiles, and the localization of histone deacetylase 3, at IRF1. While MEN1 knockdown does not impact the rate of transcription, IRF1 heteronuclear transcripts become enriched in MEN1-depleted cells. The processed mRNA and translated protein product are concomitantly reduced, and the antiviral state is attenuated. Additionally, the transcription start site at the IRF1 promoter is disrupted in the MEN1-depleted cells. The H3K4 demethylase, lysine specific demethylase 1, is also associated with IRF1, and its inhibition alters H3K4 methylation and disrupts the transcription start site as well. Conclusions: Taken together, the data indicate that MEN1 contributes to STAT1-activated gene expression in a novel manner that includes defining the transcription start site and RNA processing. http://www.epigeneticsandchromatin.com/content/5/1/2 Lauren Auriemma Shaili Shah Lara Linden Melissa Henriksen Epigenetics & Chromatin 2012, null:2 2012-01-12T00:00:00Z doi:10.1186/1756-8935-5-2 /content/figures/1756-8935-5-2-toc.gif Epigenetics & Chromatin 1756-8935 ${item.volume} 2 2012-01-12T00:00:00Z XML The integrity of the genome is continuously challenged by both endogenous and exogenous DNA damaging agents. These damaging agents can induce a wide variety of lesions in the DNA, such as double strand breaks, single strand breaks, oxidative lesions and pyrimidine dimers. The cell has evolved intricate DNA damage response mechanisms to counteract the genotoxic effects of these lesions. The two main features of the DNA damage response mechanisms are cell-cycle checkpoint activation and, at the heart of the response, DNA repair. For both damage signalling and repair, chromatin remodelling is most likely a prerequisite. Here, we discuss current knowledge on chromatin remodelling with respect to the cellular response to DNA damage, with emphasis on the response to lesions resolved by nucleotide excision repair. We will discuss the role of histone modifications as well as their displacement or exchange in nucleotide excision repair and make a comparison with their requirement in transcription and double strand break repair. http://www.epigeneticsandchromatin.com/content/1/1/9 Christoffel Dinant Adriaan Houtsmuller Wim Vermeulen Epigenetics & Chromatin 2008, null:9 2008-11-12T00:00:00Z doi:10.1186/1756-8935-1-9 /content/figures/1756-8935-1-9-toc.gif Epigenetics & Chromatin 1756-8935 ${item.volume} 9 2008-11-12T00:00:00Z XML Polycomb Group proteins are important epigenetic regulators of gene expression. Epigenetic control by polycomb Group proteins involves intrinsic as well as associated enzymatic activities. Polycomb target genes change with cellular context, lineage commitment and differentiation status, revealing dynamic regulation of polycomb function. It is currently unclear how this dynamic modulation is controlled and how signaling affects polycomb-mediated epigenetic processes at the molecular level. Experimental evidence on regulation of polycomb function by post-translational mechanisms is steadily emerging: Polycomb Group proteins are targeted for ubiquitylation, sumoylation and phosphorylation. In addition, specific Polycomb Group proteins modify other (chromatin) associated proteins via similar post-translational modifications. Such modifications affect protein function by affecting protein stability, protein-protein interactions and enzymatic activities. Here, we review current insights in covalent modification of Polycomb Group proteins in the context of protein function and present a tentative view of integrated signaling to chromatin in the context of phosphorylation. Clearly, the available literature reveals just the tip of the iceberg, and exact molecular mechanisms in, and the biological relevance of post-translational regulation of polycomb function await further elucidation. Our understanding of causes and consequences of post-translational modification of polycomb proteins will gain significantly from in vivo validation experiments. Impaired polycomb function has important repercussions for stem cell function, development and disease. Ultimately, increased understanding of signaling to chromatin and the mechanisms involved in epigenetic remodeling will contribute to the development of therapeutic interventions in cell fate decisions in development and disease. http://www.epigeneticsandchromatin.com/content/2/1/10 Hanneke Niessen Jeroen Demmers Jan Willem Voncken Epigenetics & Chromatin 2009, null:10 2009-09-01T00:00:00Z doi:10.1186/1756-8935-2-10 /content/figures/1756-8935-2-10-toc.gif Epigenetics & Chromatin 1756-8935 ${item.volume} 10 2009-09-01T00:00:00Z XML Background: Endogenous retroviruses (ERVs) are parasitic sequences whose derepression is associated with cancer and genomic instability. Many ERV families are silenced in mouse embryonic stem cells (mESCs) via SETDB1-deposited trimethylated lysine 9 of histone 3 (H3K9me3), but the mechanism of H3K9me3-dependent repression remains unknown. Multiple proteins, including members of the heterochromatin protein 1 (HP1) family, bind H3K9me2/3 and are involved in transcriptional silencing in model organisms. In this work, we address the role of such H3K9me2/3 "readers" in the silencing of ERVs in mESCs. Results: We demonstrate that despite the reported function of HP1 proteins in H3K9me-dependent gene repression and the critical role of H3K9me3 in transcriptional silencing of class I and class II ERVs, the depletion of HP1α, HP1β and HP1γ, alone or in combination, is not sufficient for derepression of these elements in mESCs. While loss of HP1α or HP1β leads to modest defects in DNA methylation of ERVs or spreading of H4K20me3 into flanking genomic sequence, respectively, neither protein affects H3K9me3 or H4K20me3 in ERV bodies. Furthermore, using novel ERV reporter constructs targeted to a specific genomic site, we demonstrate that, relative to Setdb1, knockdown of the remaining known H3K9me3 readers expressed in mESCs, including Cdyl, Cdyl2, Cbx2, Cbx7, Mpp8, Uhrf1 and Jarid1a-c, leads to only modest proviral reactivation. Conclusion: Taken together, these results reveal that each of the known H3K9me3-binding proteins is dispensable for SETDB1-mediated ERV silencing. We speculate that H3K9me3 might maintain ERVs in a silent state in mESCs by directly inhibiting deposition of active covalent histone marks. http://www.epigeneticsandchromatin.com/content/4/1/12 Irina Maksakova Preeti Goyal Jorn Bullwinkel Jeremy Brown Misha Bilenky Dixie Mager Prim Singh Matthew Lorincz Epigenetics & Chromatin 2011, null:12 2011-07-20T00:00:00Z doi:10.1186/1756-8935-4-12 /content/figures/1756-8935-4-12-toc.gif Epigenetics & Chromatin 1756-8935 ${item.volume} 12 2011-07-20T00:00:00Z XML Background: In self-renewing, pluripotent cells, bivalent chromatin modification is thought to silence (H3K27me3) lineage control genes while 'poising' (H3K4me3) them for subsequent activation during differentiation, implying an important role for epigenetic modification in directing cell fate decisions. However, rather than representing an equivalently balanced epigenetic mark, the patterns and levels of histone modifications at bivalent genes can vary widely and the criteria for identifying this chromatin signature are poorly defined. Results: Here, we initially show how chromatin status alters during lineage commitment and differentiation at a single well characterised bivalent locus. In addition we have determined how chromatin modifications at this locus change with gene expression in both ensemble and single cell analyses. We also show, on a global scale, how mRNA expression may be reflected in the ratio of H3K4me3/H3K27me3. Conclusions: While truly 'poised' bivalently modified genes may exist, the original hypothesis that all bivalent genes are epigenetically premarked for subsequent expression might be oversimplistic. In fact, from the data presented in the present work, it is equally possible that many genes that appear to be bivalent in pluripotent and multipotent cells may simply be stochastically expressed at low levels in the process of multilineage priming. Although both situations could be considered to be forms of 'poising', the underlying mechanisms and the associated implications are clearly different. http://www.epigeneticsandchromatin.com/content/4/1/9 Marco De Gobbi David Garrick Magnus Lynch Douglas Vernimmen Jim Hughes Nicolas Goardon Sidinh Luc Karen Lower Jacqueline Sloane-Stanley Cristina Pina Shamit Soneji Raffaele Renella Tariq Enver Stephen Taylor Sten Eirik Jacobsen Paresh Vyas Richard Gibbons Douglas Higgs Epigenetics & Chromatin 2011, null:9 2011-06-06T00:00:00Z doi:10.1186/1756-8935-4-9 Are bivalently modified genes “poised” for expression? The hypothesis that bivalently modified genes are pre-marked for subsequent activation during differentiation is questioned as being over-simplistic, as further light is shed on the generation of bivalent chromatin domains during cell fate decisions. /content/figures/1756-8935-4-9-toc.gif Epigenetics & Chromatin 1756-8935 ${item.volume} 9 2011-06-06T00:00:00Z XML Background: Genome-wide mappings of nucleosome occupancy in different species have shown presence of well-positioned nucleosomes. While the DNA sequences may help decide their locations, the observed positions in vivo are end-results of chromatin remodeling, the state of gene activity and binding of the sequence-specific factors to the DNA, all of which influence nucleosome positions. Thus, the observed nucleosome locations in vivo do not reflect the true contribution of DNA sequence to the mapped position. Moreover, the naturally occurring nucleosome-positioning sequences are known to guide multiple translational positionings. Results: We show that yeast SNR6, a gene transcribed by RNA polymerase III, constitutes nucleosome-positioning sequence. In the absence of a chromatin remodeler or any factor binding, the gene sequence confers a unique rotational phase to nucleosomes in the gene region, and directs assembly of several translationally positioned nucleosomes on ~1.2 kb DNA from the gene locus, including the short ~250 bp gene region. Mapping of all these gene sequence-directed nucleosome positions revealed that the array of nucleosomes in the gene upstream region occupy the same positions as those observed in vivo but the nucleosomes on the gene region can be arranged in three distinct registers. Two of these arrangements differ from each other in the position of only one nucleosome, and match with the nucleosome positions on the gene in repressed and active states in vivo, where the gene-specific factor is known to occupy the gene in both the states. The two positions are interchanged by an ATP-dependent chromatin remodeler in vivo. The third register represents the positions which block the access of the factor to the gene promoter elements. Conclusion: On a gene locus, multiple nucleosome positions are directed by a gene sequence to provide a pool of possibilities, out of which the preferred ones are selected by the chromatin remodeler and transcription factor of the gene under different states of activity of the gene. http://www.epigeneticsandchromatin.com/content/2/1/4 Vinesh Vinayachandran Rama-Haritha Pusarla Purnima Bhargava Epigenetics & Chromatin 2009, null:4 2009-03-16T00:00:00Z doi:10.1186/1756-8935-2-4 /content/figures/1756-8935-2-4-toc.gif Epigenetics & Chromatin 1756-8935 ${item.volume} 4 2009-03-16T00:00:00Z XML Background: Gene regulation in eukaryotes is a complex process entailing the establishment of transcriptionally silent chromatin domains interspersed with regions of active transcription. Imprinted domains consist of clusters of genes, some of which exhibit parent-of-origin dependent monoallelic expression, while others are biallelic. The Kcnq1 imprinted domain illustrates the complexities of long-range regulation that coexists with local exceptions. A paternally expressed repressive non-coding RNA, Kcnq1ot1, regulates a domain of up to 750 kb, encompassing 14 genes. We study how the Kcnq1 gene, initially silenced by Kcnq1ot1, undergoes tissue-specific escape from imprinting during development. Specifically, we uncover the role of chromosome conformation during these events. Results: We show that Kcnq1 transitions from monoallelic to biallelic expression during mid gestation in the developing heart. This transition is not associated with the loss of methylation on the Kcnq1 promoter. However, by exploiting chromosome conformation capture (3C) technology, we find tissue-specific and stage-specific chromatin loops between the Kcnq1 promoter and newly identified DNA regulatory elements. These regulatory elements showed in vitro activity in a luciferase assay and in vivo activity in transgenic embryos. Conclusions: By exploring the spatial organization of the Kcnq1 locus, our results reveal a novel mechanism by which local activation of genes can override the regional silencing effects of non-coding RNAs. http://www.epigeneticsandchromatin.com/content/4/1/21 Lisa Korostowski Anjali Raval Gillian Breuer Nora Engel Epigenetics & Chromatin 2011, null:21 2011-11-15T00:00:00Z doi:10.1186/1756-8935-4-21 /content/figures/1756-8935-4-21-toc.gif Epigenetics & Chromatin 1756-8935 ${item.volume} 21 2011-11-15T00:00:00Z XML