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Review
. 2024 May 6;223(5):e202311021.
doi: 10.1083/jcb.202311021. Epub 2024 Mar 20.

Crosstalk within and beyond the Polycomb repressive system

Tianyi Hideyuki Shi  1 , Hiroki Sugishita  1   2 , Yukiko Gotoh  1   2
Affiliations
Review

Crosstalk within and beyond the Polycomb repressive system

Tianyi Hideyuki Shi et al. J Cell Biol. .

Abstract

The development of multicellular organisms depends on spatiotemporally controlled differentiation of numerous cell types and their maintenance. To generate such diversity based on the invariant genetic information stored in DNA, epigenetic mechanisms, which are heritable changes in gene function that do not involve alterations to the underlying DNA sequence, are required to establish and maintain unique gene expression programs. Polycomb repressive complexes represent a paradigm of epigenetic regulation of developmentally regulated genes, and the roles of these complexes as well as the epigenetic marks they deposit, namely H3K27me3 and H2AK119ub, have been extensively studied. However, an emerging theme from recent studies is that not only the autonomous functions of the Polycomb repressive system, but also crosstalks of Polycomb with other epigenetic modifications, are important for gene regulation. In this review, we summarize how these crosstalk mechanisms have improved our understanding of Polycomb biology and how such knowledge could help with the design of cancer treatments that target the dysregulated epigenome.

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Conflict of interest statement

Disclosures: T.H. Shi reported “other” from the Japan Agency for Medical Research and Development, the Japan Society for the Promotion of Science, the Uehara Memorial Foundation, and the International Research Center for Neurointelligence during the conduct of the study. H. Sugishita reported grants from Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science, the Uehara Memorial Foundation, and the International Research Center for Neurointelligence, The University of Tokyo Institutes for Advanced Study during the conduct of the study. Y. Gotoh reported grants from Japan Agency for Medical Research and Development-CREST, Ministry of Education, Culture, Sports, Science and Technology-Japan Society for the Promotion of Science, and the Uehara Memorial Foundation during the conduct of the study.

Figures

Figure 1.
Figure 1.
The canonical mode of action of the Polycomb repressive system. (A) ncPRC1 is recruited to target sites via mechanisms enabled by its miscellaneous accessory factors. The catalytic activity of RING1B is stimulated by the RYBP or YAF subunit, resulting in deposition of H2AK119ub. PRC2.1 and PRC2.2 are subsequently recruited, at least via the recognition of H2AK119ub by the JARID2 subunit of PRC2.2, and they deposit H3K27me3 via their catalytic subunit, EZH2. H3K27me3 in turn recruits cPRC1 via the chromodomain of cPRC1’s CBX subunit. cPRC1, which has very low in vivo ubiquitylation activity, promotes nucleosome compaction and long-range interactions between cPRC1-bound sites. The relative direct contribution of H2AK119ub, H3K37me3, and cPRC1-mediated chromatin interactions to gene repression appears to be context dependent and is not fully understood (Kim and Kingston, 2022). (B) Initiation mechanisms of PRCs binding to target genes. (a) Transcriptional inactivation promotes assembly of ncPRC1, especially ncPRC1.1, whose KDM2B subunit is already bound to CGI-associated promoters. H2AK119ub deposited by ncPRC1 then recruits PRC2. This is thought to be the most common mechanism of initiation of Polycomb-mediated repression of gene promoters in mammals. (b) PRCs can be recruited by transcription factors (TFs). For example, ncPRC1.6 is recruited by its subunit, the MGA/MAX heterodimer, to germline-specific genes that contain E-box motifs (Endoh et al., 2017). Pioneer TFs such as FOXA1/2/3 and OCT4 can cooperate with PRDM factors to recruit PRC1 to lineage-incompatible enhancers, likely by direct physical interaction with RING1B (Matsui et al., 2024). (c) ncPRC1.3/ncPRC1.5 can be recruited by chromosome-bound regulatory long non-coding RNA (lncRNA), for example, XIST on the inactivated X chromosome (Almeida et al., 2017; Pintacuda et al., 2017), and AIRN and KCNQ1OT1 on autosomes (Schertzer et al., 2019). This interaction is mediated by the adaptor protein heterogeneous nuclear ribonucleoprotein K (HNRNPK) and results in formation of transcriptionally repressed domains at large chromosomal regions.
Figure 2.
Figure 2.
Crosstalk with H3K4 methylation. (A) Bivalent promoters comarked with H3K27me3 and H3K4me3 are abundant in ESCs, in which they are temporarily repressed but are later resolved into monovalent promoters possessing either the active H3K4me3 mark or the repressive H3k27me3 mark. Despite this general trend, differentiated cells also possess bivalent promoters, and this resolution is not always absolute; transcription activity depends on the relative levels of H3K4me3 of H3K27me3 (Jadhav et al., 2016, 2020). (B) While the H3K4me3 mark deposited by KMT2A/B is antagonistic to the H3K27me3 mark deposited by PRC2 at bivalent promoters, KMT2A/B is more robustly recruited to active monovalent promoters by its MEN1 accessory factor. MEN1 inhibition or KO thus augments KMT2A/B recruitment to bivalent promoters and promotes gene repression. PRC2 inhibition has the same effect on bivalent promoters, and the combined inhibition of PRC2 and MEN1 leads to more effective activation of bivalent promoters (Sparbier et al., 2023).
Figure 3.
Figure 3.
Crosstalk with H3K36 methylation. (A) Although PCL1/2/3 all possess a Tudor domain that recognizes H3K36me3, H3K36me2/3 inhibits EZH2 catalytic activity, and thus H3K27me3 and H3K36me2/3 usually do not colocalize. PCL3 is unique in that it was shown to be able to recruit NO66, a H3K36me2/3 demethylase, and thus could potentially help to initiate PRC2-mediated repression of hitherto H3K36me2/3 marked, actively transcribed genes. (B) The oncohistone H3K27M inhibits PRC2 activity and thus depletes H3K27me3 at weak PRC2 targets. Invasion of H3K36me2, which is deposited by NSD1/2, into these regions results in transcription activation, which is mediated at least in part by LEDGF and HDGF2. (C) NSD1/2 double KO largely recapitulates the effect of H3K36M overexpression in that they both deplete intergenic H3K36me2, resulting in redistribution of PRC2 from their canonical targets to intergenic regions and non-canonical genic targets and hence their up- and downregulation, respectively (Rajagopalan et al., 2021). (D) H3K36me2 depletion improves iPSC induction efficiency by promoting the simultaneous silencing of mesenchymal genes and activation of epithelial/pluripotency genes. Epithelial/pluripotency gene activation depends on the DNA hypomethylation facilitated by reduced DNMT3A/B recruitment and increased TET activity. Loss of H3K36me2 promotes PRC2 recruitment and thus silencing of mesenchymal genes (Hoetker et al., 2023). Additionally, the catalytic-independent activity of TET1 (Chrysanthou et al., 2022) may also contribute to PRC2 recruitment.
Figure 4.
Figure 4.
Crosstalk with DNAme and H3K9me3. (A) The short isoform of DNMT3A (DNMT3A2) is expressed in ESCs and it is targeted to H3K36me2-marked intergenic regions via its PWWP domain. The long isoform (DNMT3A1), which is the predominant form in specific adult cell types, including neurons but not glia, additionally processes a UIM domain that targets it to H2AK119ub-marked flanking regions of bivalent promoters. Loss-of-function of this domain results in hypomethylation of these promoters concomitant with both up- and downregulation of gene expression (Gu et al., 2022). (B) During ESC-to-EpiLC differentiation, some non-CGI PRC2 targets acquire de novo DNAme. DNAme evicts PRC2 at some sites (right) but not at the others (left), providing an explanation for the dual role of DNAme in transcription regulation (Albert et al., 2023, Preprint). (C) Germline genes are repressed by default and are only activated during germ cell development. Before implantation, this repression depends on ncPRC1.6 and SETDB1. ncPRC1.6 is recruited by sequence-specific recognition of E-box and E2F motifs by its MGA/MAX and E2F6 subunits, respectively, and SETDB1 recruitment at least partially depends on ncPRC1.6. ncPRC1.6 and SETDB1 are required for efficient recruitment of DNMT3A/B, which establishes post-implantation de novo DNA methylation that contributes to long-term repression of germ-line genes (Mochizuki et al., 2021). (D) While the maternal PCH is consistently marked by H3K9me3 that represses the transcription of the underlying major satellite sequences, the patPCH is initially devoid of H3K9me3 and instead repressed by cPRC1 upon fertilization. The gradual accumulation of H3K9me3 deposited initially by SUV39H2 and then by SUV39H1 at patPCH evicts cPRC1, resulting in a transition from cPRC1-dependent to H3K9me3-dependent repression of pericentromeric major satellites. However, the initial H3K9me3 deposited by SUV39H2 appears to be compatible with gene expression and might be required for the transient activation of some two-cell or four-cell stage-specific genes (Burton et al., 2020).
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