Histone methylation by PRC2 is inhibited by active chromatin marks

Chromatin modifiers serve as regulatory switches that control the cell cycle, maintain pluripotency and drive differentiation and development. Positive feedback mechanisms help to pass on transcriptional information from one generation of cells to the next one. The polycomb repressive complex 2 (PRC2) is responsible for methylation of histone H3 at lysine 27, a typical mark of repressive chromatin. De novo methylation requires sequence-specific recruitment factors. In contrast, propagation and inheritance of the H3K27me3 mark after replication relies on a self-maintaining feedback loop: direct interaction of PRC2 with existing H3K27me3 marks triggers an allosteric stimulation of the methyltransferase activity and results in efficient modification of new histones that have been incorporated in repressive chromatin regions. In this study we present an inhibitory mechanism that limits the spread of H3K27 methylation and protects active chromatin by breaking the positive feedback loop. PRC2 is allosterically inhibited by nucleosomes carrying active chromatin modifications such as H3K4me3 or H3K36me2/3. The mechanism is conserved in mammals, flies and even plants. In addition plants have distinct PRC2 subcomplexes and can modulate their specificity by the choice of the Su(z)12 homologue. Furthermore, we have identified Nurf55 as another histone binding module in the PRC2 complex that recognizes unmodified histone H3 but not H3K4me3. Taken together, H3K27 methylation presents itself as a typical bistable switch. It is driven by the positive feedback loop in PRC2 activation and limited by active mark inhibition. Numerous chromatin modifying complexes recognize their own products and positive feedback loops are a common mechanism. We postulate that all these complexes need an additional inhibitory switch that prevents spreading of histone modifications over the entire genome

Perspectives on ENCODE

The Encylopedia of DNA Elements (ENCODE) Project launched in 2003 with the long-term goal of developing a comprehensive map of functional elements in the human genome. These included genes, biochemical regions associated with gene regulation (for example, transcription factor binding sites, open chromatin, and histone marks) and transcript isoforms. The marks serve as sites for candidate cis-regulatory elements (cCREs) that may serve functional roles in regulating gene expression1. The project has been extended to model organisms, particularly the mouse. In the third phase of ENCODE, nearly a million and more than 300,000 cCRE annotations have been generated for human and mouse, respectively, and these have provided a valuable resource for the scientific community.11Nsciescopu

Expanded encyclopaedias of DNA elements in the human and mouse genomes

AbstractThe human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded analysis of the cell and tissue repertoires of RNA transcription, chromatin structure and modification, DNA methylation, chromatin looping, and occupancy by transcription factors and RNA-binding proteins. Here we summarize these efforts, which have produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www.encodeproject.org), including phase II ENCODE1 and Roadmap Epigenomics2 data. We have developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements, covering 7.9 and 3.4% of their respective genomes, by integrating selected datatypes associated with gene regulation, and constructed a web-based server (SCREEN; http://screen.encodeproject.org) to provide flexible, user-defined access to this resource. Collectively, the ENCODE data and registry provide an expansive resource for the scientific community to build a better understanding of the organization and function of the human and mouse genomes.11Nsciescopu