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

Molecular Mechanisms Directing PRC2 Recruitment and H3K27 Methylation

Precise control of gene expression is fundamental to cell function and development. Although ultimately gene expression relies on DNA-binding transcription factors to guide the activity of the transcription machinery to genes, it has also become clear that chromatin and histone post-translational modification have fundamental roles in gene regulation. Polycomb repressive complexes represent a paradigm of chromatin-based gene regulation in animals. The Polycomb repressive system comprises two central protein complexes, Polycomb repressive complex 1 (PRC1) and PRC2, which are essential for normal gene regulation and development. Our early understanding of Polycomb function relied on studies in simple model organisms, but more recently it has become apparent that this system has expanded and diverged in mammals. Detailed studies are now uncovering the molecular mechanisms that enable mammalian PRC1 and PRC2 to identify their target sites in the genome, communicate through feedback mechanisms to create Polycomb chromatin domains and control transcription to regulate gene expression. In this Review, we discuss and contextualize the emerging principles that define how this fascinating chromatin-based system regulates gene expression in mammals.

The molecular principles of gene regulation by Polycomb repressive complexes.

Histone H2AK119 Mono-Ubiquitination Is Essential for Polycomb-Mediated Transcriptional Repression.

More than 80 years ago, the first Polycomb-related phenotype was identified in Drosophila melanogaster. Later, a group of diverse genes collectively called Polycomb group (PcG) genes were identified based on common mutant phenotypes. PcG proteins, which are well-conserved in animals, were originally characterized as negative regulators of gene transcription during development and subsequently shown to function in various biological processes; their deregulation is associated with diverse phenotypes in development and in disease, especially cancer. PcG proteins function on chromatin and can form two distinct complexes with different enzymatic activities: Polycomb repressive complex 1 (PRC1) is a histone ubiquitin ligase and PRC2 is a histone methyltransferase. Recent studies have revealed the existence of various mutually exclusive PRC1 and PRC2 variants. In this Review, we discuss new concepts concerning the biochemical and molecular functions of these new PcG complex variants, and how their epigenetic activities are involved in mammalian development and cancer. The histone modifiers Polycomb repressive complex 1 (PRC1) and PRC2 have important roles in development and disease, especially cancer. Recent studies have revealed the existence of various mutually exclusive PRC1 and PRC2 variants, and provided new insights into their molecular functions and physiological importance.

The roles of Polycomb repressive complexes in mammalian development and cancer.

A Family of Vertebrate-Specific Polycombs Encoded by the LCOR/LCORL Genes Balance PRC2 Subtype Activities.

Polycomb repressive complex 2 (PRC2) is a conserved chromatin regulator that is responsible for the methylation of histone H3 lysine 27 (H3K27). PRC2 is essential for normal development and its loss of function thus results in a range of developmental phenotypes. Here, we review the latest advances in our understanding of mammalian PRC2 activity and present an updated summary of the phenotypes associated with its loss of function in mice. We then discuss recent studies that have highlighted regulatory interplay between the modifications laid down by PRC2 and other chromatin modifiers, including NSD1 and DNMT3A. Finally, we propose a model in which the dysregulation of these modifications at intergenic regions is a shared molecular feature of genetically distinct but highly phenotypically similar overgrowth syndromes in humans.

/pdf/prc2-functions-in-development-and-congenital-disorders-1gmum3c7ap.pdf

PRC2 functions in development and congenital disorders.

Driver mutations in genes encoding histone H3 proteins resulting in p.Lys27Met substitutions (H3-K27M) are frequent in pediatric midline brain tumors. However, the precise mechanisms by which H3-K27M causes tumor initiation remain unclear. Here, we use human hindbrain neural stem cells to model the consequences of H3.3-K27M on the epigenomic landscape in a relevant developmental context. Genome-wide mapping of epitope-tagged histone H3.3 revealed that both the wild type and the K27M mutant incorporate abundantly at pre-existing active enhancers and promoters, and to a lesser extent at Polycomb repressive complex 2 (PRC2)-bound regions. At active enhancers, H3.3-K27M leads to focal H3K27ac loss, decreased chromatin accessibility and reduced transcriptional expression of nearby neurodevelopmental genes. In addition, H3.3-K27M deposition at a subset of PRC2 target genes leads to increased PRC2 and PRC1 binding and augmented transcriptional repression that can be partially reversed by PRC2 inhibitors. Our work suggests that, rather than imposing de novo transcriptional circuits, H3.3-K27M drives tumorigenesis by locking initiating cells in their pre-existing, immature epigenomic state, via disruption of PRC2 and enhancer functions.

Simultaneous disruption of PRC2 and enhancer function underlies histone H3.3-K27M oncogenic activity in human hindbrain neural stem cells

Weaver syndrome (WS) is a developmental overgrowth and intellectual disability disorder caused by heterozygous mutations in EZH2. EZH2 encodes the enzymatic subunit of Polycomb Repressive Complex 2 (PRC2) which mediates methylation of histone H3 lysine residue 27 (H3K27). Although PRC2 has been extensively studied at the molecular level, the effects of WS-associated EZH2 mutations on cells remain poorly understood. In this study, we expressed WS-associated EZH2 variants in mouse embryonic stem cells and found that they have dominant negative effects on Polycomb repressive function. These EZH2 variants decrease H3K27me2/3 and increase H3K27ac levels at intergenic regions, causing global chromatin decompaction and transcriptional upregulation of sensitive Polycomb target genes. Interestingly, a contrasting EZH2 variant linked to growth restriction caused opposing changes in H3K27 methylation and acetylation, and repressed the same cohort of Polycomb target genes. Our study provides insights into the molecular mechanisms of EZH2-mutant human growth disorders, revealing the opposing changes in chromatin and transcription associated with Weaver syndrome and growth restriction, respectively.

/pdf/dominant-negative-and-directional-dysregulation-of-polycomb-6woa9tzr.pdf

Dominant negative and directional dysregulation of Polycomb function in EZH2-mutant human growth disorders

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A Family of Vertebrate-Specific Polycombs Encoded by the LCOR/LCORL Genes Balance PRC2 Subtype Activities.

PRC2 functions in development and congenital disorders.

Simultaneous disruption of PRC2 and enhancer function underlies histone H3.3-K27M oncogenic activity in human hindbrain neural stem cells

Dominant negative and directional dysregulation of Polycomb function in EZH2-mutant human growth disorders