JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells

Abstract

The Polycomb group (PcG) proteins have an important role in controlling the expression of genes essential for development, differentiation and maintenance of cell fates. The Polycomb repressive complex 2 (PRC2) is believed to regulate transcriptional repression by catalysing the di- and tri-methylation of lysine 27 on histone H3 (H3K27me2/3). At present, it is unknown how the PcG proteins are recruited to their target promoters in mammalian cells. Here we show that PRC2 forms a stable complex with the Jumonji- and ARID-domain-containing protein, JARID2 (ref. 4). Using genome-wide location analysis, we show that JARID2 binds to more than 90% of previously mapped PcG target genes. Notably, we show that JARID2 is sufficient to recruit PcG proteins to a heterologous promoter, and that inhibition of JARID2 expression leads to a major loss of PcG binding and to a reduction of H3K27me3 levels on target genes. Consistent with an essential role for PcG proteins in early development, we demonstrate that JARID2 is required for the differentiation of mouse embryonic stem cells. Thus, these results demonstrate that JARID2 is essential for the binding of PcG proteins to target genes and, consistent with this, for the proper differentiation of embryonic stem cells and normal development.

Epigenetic Mechanisms in Inflammation

“…The binding of PRC1 to chromatin is usually dependent on the activity of PRC2. However, PRC2 may use different recruitment mechanisms to target different downstream genes (Peng et al, 2009;Shen et al, 2009;Landeira et al, 2010;Li et al, 2010;Pasini et al, 2010). PRC2 forms a stable complex with the transcriptional repressor JARID2, a member of the Jumonji C (JmjC) and ARID domain protein family (Cheng and Blumenthal, 2010).…”

Targeting the epigenome in malignant pleural mesothelioma

“…These histone marks coincide with recruitment of CRC, formation of heterochromatin -frequently in the context of DNA hypermethylation, and repression of gene expression (82,83). Several proteins such as JARID2 and additional sex comb-like (ASXL) family members physically interact with EZH2 and SUZ12 to target PRC-2 to polycomb response elements (PRE) throughout the genome (84,85). Although often associated with promoter hypermethylation, polycomb-mediated gene silencing may occur independent of DNA methylation (86,87), typically in the context of bivalent chromatin, exhibiting occupancy of PcG proteins and simultaneous activation (H3K4Me3) and repressive (H3K27Me3) histone marks.…”

Structure of the PRC2 complex and application to drug discovery

“…JARID2 is a transcriptional repressor [29] and a member of the Jumonji C (JmjC) and ARID domain protein family of histone demethylases, yet it lacks the key residues necessary for cofactor binding and is devoid of enzymatic activity [1,21,30] . 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] .…”

“…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] .…”