PRC2 is high maintenance

Abstract

As the process that silences gene expression ensues during development, the stage is set for the activity of Polycomb-repressive complex 2 (PRC2) to maintain these repressed gene profiles. PRC2 catalyzes a specific histone posttranslational modification (hPTM) that fosters chromatin compaction. PRC2 also facilitates the inheritance of this hPTM through its self-contained “write and read” activities, key to preserving cellular identity during cell division. As these changes in gene expression occur without changes in DNA sequence and are inherited, the process is epigenetic in scope. Mutants of mammalian PRC2 or of its histone substrate contribute to the cancer process and other diseases, and research into these aberrant pathways is yielding viable candidates for therapeutic targeting. The effectiveness of PRC2 hinges on its being recruited to the proper chromatin sites; however, resolving the determinants to this process in the mammalian case was not straightforward and thus piqued the interest of many in the field. Here, we chronicle the latest advances toward exposing mammalian PRC2 and its high maintenance.

Differentiating Drosophila female germ cells initiate Polycomb silencing by altering PRC2 sampling

“…Unfortunately, studying the establishment of PRC2 specificity in early embryos is hampered by difficulties in purifying and genetically manipulating a short-lived transition state controlled by both a maternal and zygotic supply of PcG proteins. Nevertheless, many studies have investigated factors controlling PcG targeting specificity in other cell types in both flies and mammals, which may offer clues into how PcG targeting specificity is first induced in early embryos (recently reviewed in (Kassis et al, 2017;Kuroda et al, 2020;Laugesen et al, 2019;Yu et al, 2019).…”

“…In mammals, multiple mechanisms have been proposed to contribute to PRC1 and PRC2 recruitment to CGIs including DNA shape, nucleosome spacing, histone tail modifications including a "bivalent" combination of H3K27me3 and H3K4me3, and interactions with RNA (Yu et al, 2019). Notably, mouse Kdm2 subunits of PRC1 and the Pcl subunits of PRC2 specifically bind CGI sequences in vitro and have been proposed to initially recruit each complex to CGIs in vivo (Farcas et al, 2012;He et al, 2013;Li et al, 2017;Perino et al, 2018;Wu et al, 2013).…”

Domain model explains propagation dynamics and stability of K27 and K36 methylation landscapes

“…Intriguingly, PRC2 also methylates its binding partner JARID2 on a K27 mimicking peptide that also can activate the enzyme allosterically (Sanulli et al, 2015). However, other factors including genomic features, bound RNA and H2A ubiquitination by PRC1 are likely to also contribute to K27me3 maintenance (King et al, 2018;Laugesen et al, 2019;Yu et al, 2019). In Drosophila, self-propagation is not sufficient for K27me3 maintenance as sequence elements directing PRC recruitment are also required (Coleman and Struhl, 2017;Laprell et al, 2017).…”

The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+T cells

“…Among those, Ezh2 emerged as a potentially relevant target of DOT1L that could explain part of the derepression of genes in Dot1L-KO cells ( Table 1). EZH2 is part of the Polycomb-repressive complex 2 (PRC2), which deposits H3K27me3 54,55,56,57,58,59 , a mark involved in repression of developmentallyregulated genes and in switching off naïve and memory genes during terminal differentiation of effector CD8 + T cells 40,60 . Although the change in Ezh2 mRNA expression was modest between WT and KO (Sup Fig.…”