The molecular principles of gene regulation by Polycomb repressive complexes

Abstract

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 contextualise the emerging principles that define how this fascinating chromatin-based system regulates gene expression in mammals.

Maternal SMCHD1 controls both imprinted Xist expression and imprinted X chromosome inactivation

“…In the absence of SMCHD1, H3K27me3 spreads and H3K9me3 is lost on the Xi ( Jansz et al, 2018b ; Ichihara et al, 2021 ). SMCHD1’s role at its targets may be to facilitate the positive feedback loops of Polycomb repression ( Blackledge and Klose, 2021 ), concentrating the Polycomb machinery, Polycomb marks and repressors at specific loci to both reach a threshold required for efficient silencing as well as avoid ectopic redistribution of Polycomb. This mechanism would be conceptually close to what has been proposed for plant MORC proteins, GKHL ATPases like SMCHD1, which are proposed to anchor a chromatin silencing pathway to target loci ( Xue et al, 2021 ).…”

The tandem repeat modules of Xist lncRNA: a swiss army knife for the control of X-chromosome inactivation

“…The dynamics of accumulation of PcG marks over active genes could be attributed to a direct role of Repeat A in PcG recruitment to genes [13] or simply be a secondary event to the transcriptional silencing imposed by the Repeat A/SPEN pathway. We favor this second hypothesis given that the transcriptional silencing of CG-rich promoters, such as the ones for many X-linked genes, creates a chromatin environment permissive for PRC2 recruitment [38][39][40]. In this respect, mapping H3K27me3/H2AK119ub enrichment over the Xi in Spen SPOC mutants will be important to disentangle between a direct or a passive role for Repeat A in PcG recruitment to X-linked genes undergoing silencing.…”

Single-cell profiling of transcriptome and histone modifications with EpiDamID

“…Wang et al, 2004), and H3K27me3 is the histone PTM deposited by PRC2 (R. Cao et al, 2002;Czermin et al, 2002;Kuzmichev et al, 2002;Müller et al, 2002). Both PRC1 and PRC2 have key roles in gene regulation during stem cell differentiation and early embryonic development (see (Piunti & Shilatifard, 2021) and (Blackledge & Klose, 2021) for recent reviews on this topic).…”