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 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.

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