Jarid2 Methylation via the PRC2 Complex Regulates H3K27me3 Deposition during Cell Differentiation

Abstract

SummaryPolycomb Group (PcG) proteins maintain transcriptional repression throughout development, mostly by regulating chromatin structure. Polycomb Repressive Complex 2 (PRC2), a component of the Polycomb machinery, is responsible for the methylation of histone H3 lysine 27 (H3K27me2/3). Jarid2 was previously identified as a cofactor of PRC2, regulating PRC2 targeting to chromatin and its enzymatic activity. Deletion of Jarid2 leads to impaired orchestration of gene expression during cell lineage commitment. Here, we reveal an unexpected crosstalk between Jarid2 and PRC2, with Jarid2 being methylated by PRC2. This modification is recognized by the Eed core component of PRC2 and triggers an allosteric activation of PRC2’s enzymatic activity. We show that Jarid2 methylation is important to promote PRC2 activity at a locus devoid of H3K27me3 and for the correct deposition of this mark during cell differentiation. Our results uncover a regulation loop where Jarid2 methylation fine-tunes PRC2 activity depending on the chromatin context.

Au cœur d’une complexité biologique

“…EZH2 mono-méthyle également le récepteur nucléaire et suppresseur de tumeur ROR (retinoic acid-related orphan nuclear receptor a) qui est alors reconnu par un complexe contenant une ubiquitine ligase entraînant sa dégradation [23]. EZH2 peut enfin méthy-ler JARID2 qui peut alors moduler l'activité catalytique de PRC2, créant ainsi une boucle de régulation [24].…”

Propagation of trimethylated H3K27 regulated by polycomb protein EED is required for embryogenesis, hematopoietic maintenance, and tumor suppression

“…Questions remain concerning tissue-and cell type-specificity and context-dependency of EED function, however, because despite lower levels of H3K27me3, the Eed KI/+ mice were able to survive as long as the Eed +/+ mice. Interestingly, a recent study reported that H3K27me3 propagation is regulated by the JARID2 protein, a cofactor of PRC2 (28). Future studies are needed to clarify the perplexing and multifaceted in vivo function of PRC2.…”

Structure of the PRC2 complex and application to drug discovery

“…The C-terminal half of JARID2 contains the conserved JmjC and JmjN domains, the ARID domain (a potential DNA-binding domain), and a zinc finger, while the N-terminal half contains an allosteric effect domain, a PRC2-binding region and a nucleosome-binding domain [21,[30][31][32] . How JARID2 influences PRC2, in mechanistic terms, is less well defined.…”

“…How JARID2 influences PRC2, in mechanistic terms, is less well defined. Methylated JARID2 mimics methylated H3K27me3 to recruit and activate PRC2, and knockdown/loss-of-function experiments revealed a partial mutual dependence on JARID2 and core PRC2 subunits for target binding [21,[30][31][32][33][34][35][36][37][38][39][40] . JARID2 can bind to long noncoding RNAs (lncRNAs), whose presence stimulates JARID2-EZH2 interactions in vitro and JARID2-mediated recruitment of PRC2 to chromatin in vivo [33] .…”

“…JARID2 can bind to long noncoding RNAs (lncRNAs), whose presence stimulates JARID2-EZH2 interactions in vitro and JARID2-mediated recruitment of PRC2 to chromatin in vivo [33] . JARID2 can also modulate PRC2 histone methyltransferase activity in vitro; however, whether this influence is stimulatory or inhibitory is controversial [21,[30][31][32][33]37] .…”