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Polycomb Gene Silencing Mechanisms: PRC2 Chromatin Targeting, H3K27me3 'Readout', and Phase Separation-Based Compaction

Journal

TRENDS IN GENETICS
Volume 37, Issue 6, Pages 547-565

Publisher

CELL PRESS
DOI: 10.1016/j.tig.2020.12.006

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The modulation of chromatin structure and/or modification by Polycomb repressive complexes (PRCs) plays a crucial role in partitioning the genome and regulating gene activity. PRC2 enzymatic activity and its interaction with cofactors, DNA elements, histones, RNA, and effectors such as canonical PRC1 are intricately regulated to mediate gene silencing through mechanisms like chromatin compaction and histone deacetylation. Understanding the structural architecture and regulation of PRC2, as well as the molecular mechanisms of Polycomb-mediated gene silencing, has significant implications in biology and medicine.
Modulation of chromatin structure and/or modification by Polycomb repressive complexes (PRCs) provides an important means to partition the genome into functionally distinct subdomains and to regulate the activity of the underlying genes. Both the enzymatic activity of PRC2 and its chromatin recruitment, spreading, and eviction are exquisitely regulated via interactions with cofactors and DNA elements (such as unmethylated CpG islands), histones, RNA (nascent mRNA and long noncoding RNA), and R-loops. PRC2-catalyzed histone H3 lysine 27 trimethylation (H3K27me3) is recognized by distinct classes of effectors such as canonical PRC1 and BAH module-containing proteins (notably BAHCC1 in human). These effectors mediate gene silencing by different mechanisms including phase separation-related chromatin compaction and histone deacetylation. We discuss recent advances in understanding the structural architecture of PRC2, the regulation of its activity and chromatin recruitment, and the molecular mechanisms underlying Polycomb-mediated gene silencing. Because PRC deregulation is intimately associated with the development of diseases, a better appreciation of Polycomb-based (epi)genomic regulation will have far-reaching implications in biology and medicine.

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