The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

High mobility group 1 (HMGB1) protein is both a nuclear factor and a secreted protein. In the cell nucleus it acts as an architectural chromatin-binding factor that bends DNA and promotes protein assembly on specific DNA targets. Outside the cell, it binds with high affinity to RAGE (the receptor for advanced glycation end products) and is a potent mediator of inflammation. HMGB1 is secreted by activated monocytes and macrophages, and is passively released by necrotic or damaged cells. Here we report that Hmgb1(-/-) necrotic cells have a greatly reduced ability to promote inflammation, which proves that the release of HMGB1 can signal the demise of a cell to its neighbours. Apoptotic cells do not release HMGB1 even after undergoing secondary necrosis and partial autolysis, and thus fail to promote inflammation even if not cleared promptly by phagocytic cells. In apoptotic cells, HMGB1 is bound firmly to chromatin because of generalized underacetylation of histone and is released in the extracellular medium (promoting inflammation) if chromatin deacetylation is prevented. Thus, cells undergoing apoptosis are programmed to withhold the signal that is broadcast by cells that have been damaged or killed by trauma.

Release of chromatin protein HMGB1 by necrotic cells triggers inflammation

Cisplatin, carboplatin and oxaliplatin are platinum-based drugs that are widely used in cancer chemotherapy. Platinum–DNA adducts, which are formed following uptake of the drug into the nucleus of cells, activate several cellular processes that mediate the cytotoxicity of these platinum drugs. This review focuses on recently discovered cellular pathways that are activated in response to cisplatin, including those involved in regulating drug uptake, the signalling of DNA damage, cell-cycle checkpoints and arrest, DNA repair and cell death. Such knowledge of the cellular processing of cisplatin adducts with DNA provides valuable clues for the rational design of more efficient platinum-based drugs as well as the development of new therapeutic strategies.

Cellular processing of platinum anticancer drugs.

Cytosine DNA methylation is a stable epigenetic mark that is crucial for diverse biological processes, including gene and transposon silencing, imprinting and X chromosome inactivation. Recent findings in plants and animals have greatly increased our understanding of the pathways used to accurately target, maintain and modify patterns of DNA methylation and have revealed unanticipated mechanistic similarities between these organisms. Key roles have emerged for small RNAs, proteins with domains that bind methylated DNA and DNA glycosylases in these processes. Drawing on insights from both plants and animals should deepen our understanding of the regulation and biological significance of DNA methylation.

Establishing, maintaining and modifying DNA methylation patterns in plants and animals

Gene transcription can be activated or inhibited by a reversible modification of the gene; this modification is termed an epigenetic change. This account of epigenetics in cancer reviews the mechan...

/pdf/epigenetics-in-cancer-4240m6az4l.pdf

Epigenetics in Cancer

https://www.cell.com/cell/pdf/S0092-8674(00)80797-7.pdf

Nucleosome Movement by CHRAC and ISWI without Disruption or trans-Displacement of the Histone Octamer

We report for the first time the genomics of a nuclear compartment of the eukaryotic cell. 454 sequencing and microarray analysis revealed the pattern of nucleolus-associated chromatin domains (NADs) in the linear human genome and identified different gene families and certain satellite repeats as the major building blocks of NADs, which constitute about 4% of the genome. Bioinformatic evaluation showed that NAD-localized genes take part in specific biological processes, like the response to other organisms, odor perception, and tissue development. 3D FISH and immunofluorescence experiments illustrated the spatial distribution of NAD-specific chromatin within interphase nuclei and its alteration upon transcriptional changes. Altogether, our findings describe the nature of DNA sequences associated with the human nucleolus and provide insights into the function of the nucleolus in genome organization and establishment of nuclear architecture.

https://epub.ub.uni-muenchen.de/15791/1/oa_15791.pdf

Initial genomics of the human nucleolus.

Transcription by RNA polymerase I on nucleosomal templates requires binding of the transcription termination factor TTF-I to a cognate site 160 bp upstream of the transcription start site. Binding of TTF-I is accompanied by changes in the chromatin architecture which suggests that TTF-I recruits a remodeling activity to the rDNA promoter. We have cloned a cDNA that encodes TIP5 (TTF-I-interacting protein 5), a 205 kDa protein that shares a number of important protein domains with WSTF (Williams syndrome transcription factor) and hAcf1/WCRF180, the largest subunits of human chromatin remodeling complexes hCHRAC and WCRF. TIP5 co-localizes with the basal RNA polymerase I transcription factor UBF in the nucleolus and is associated with SNF2h. The cellular TIP5–SNF2h complex, termed NoRC (nucleolar remodeling complex), induces nucleosome sliding in an ATP- and histone H4 tail-dependent fashion. The results suggest that NoRC is a novel nucleolar chromatin remodeling machine that may serve a role in the regulation of the rDNA locus.

/pdf/norc-a-novel-member-of-mammalian-iswi-containing-chromatin-39q0um4hn0.pdf

NoRC--a novel member of mammalian ISWI-containing chromatin remodeling machines.

https://www.cell.com/molecular-cell/pdf/S1097-2765(00)80314-7.pdf

ISWI Is an ATP-Dependent Nucleosome Remodeling Factor

The ATPase ISWI can be considered the catalytic core of several multiprotein nucleosome remodeling machines. Alone or in the context of nucleosome remodeling factor, the chromatin accessibility complex (CHRAC), or ACF, ISWI catalyzes a number of ATP-dependent transitions of chromatin structure that are currently best explained by its ability to induce nucleosome sliding. In addition, ISWI can function as a nucleosome spacing factor during chromatin assembly, where it will trigger the ordering of newly assembled nucleosomes into regular arrays. Both nucleosome remodeling and nucleosome spacing reactions are mechanistically unexplained. As a step toward defining the interaction of ISWI with its substrate during nucleosome remodeling and chromatin assembly we generated a set of nucleosomes lacking individual histone N termini from recombinant histones. We found the conserved N termini (the N-terminal tails) of histone H4 essential to stimulate ISWI ATPase activity, in contrast to other histone tails. Remarkably, the H4 N terminus, but none of the other tails, was critical for CHRAC-induced nucleosome sliding and for the generation of regularity in nucleosomal arrays by ISWI. Direct nucleosome binding studies did not reflect a dependence on the H4 tail for ISWI-nucleosome interactions. We conclude that the H4 tail is critically required for nucleosome remodeling and spacing at a step subsequent to interaction with the substrate.

Gernot Längst

Papers

Nucleosome Movement by CHRAC and ISWI without Disruption or trans-Displacement of the Histone Octamer

Initial genomics of the human nucleolus.

NoRC--a novel member of mammalian ISWI-containing chromatin remodeling machines.

ISWI Is an ATP-Dependent Nucleosome Remodeling Factor

Critical role for the histone H4 N terminus in nucleosome remodeling by ISWI.