Jarid2 and PRC2, partners in regulating gene expression

Abstract

The Polycomb group proteins foster gene repression profiles required for proper development and unimpaired adulthood, and comprise the components of the Polycomb-Repressive Complex 2 (PRC2) including the histone H3 Lys 27 (H3K27) methyltransferase Ezh2. How mammalian PRC2 accesses chromatin is unclear. We found that Jarid2 associates with PRC2 and stimulates its enzymatic activity in vitro. Jarid2 contains a Jumonji C domain, but is devoid of detectable histone demethylase activity. Instead, its artificial recruitment to a promoter in vivo resulted in corecruitment of PRC2 with resultant increased levels of di- and trimethylation of H3K27 (H3K27me2/3). Jarid2 colocalizes with Ezh2 and MTF2, a homolog of Drosophila Pcl, at endogenous genes in embryonic stem (ES) cells. Jarid2 can bind DNA and its recruitment in ES cells is interdependent with that of PRC2, as Jarid2 knockdown reduced PRC2 at its target promoters, and ES cells devoid of the PRC2 component EED are deficient in Jarid2 promoter access. In addition to the well-documented defects in embryonic viability upon down-regulation of Jarid2, ES cell differentiation is impaired, as is Oct4 silencing.

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).…”

Gene Silencing and Polycomb Group Proteins: An Overview of their Structure, Mechanisms and Phylogenetics

“…PRC2 is comprised of three main, strongly conserved subcomplexes: Esc and Enhancer of Zeste [E(z)]; Suppressor of Zeste 12 (Suz12); and RbAp48/Nurf-55 (Cao et al, 2002;Kuzmichev et al, 2002;Muller et al, 2002). There is some evidence that PRC2 is composed of more than just these four components (Cao and Zhang, 2004b;Kim et al, 2009;Li et al, 2010a;Pasini et al, 2010). Ring proteins consist of various domains such as dRing plus two additional conserved cores: Ring1A and Ring1B.…”

Structure of the PRC2 complex and application to drug discovery

“…The program Autodock was used to dock the PRC2 inhibitors EPZ6438, GSK126, and UNC1999 into the crystal structure of the PRC2/Inhibitor 1 complex (PDB code 5IJ7) [95] . tion of the histone chaperones RbAp46/48 with histones [25,106] , (2) the interaction of JARID2 and AEBP2 with DNA [27,30,37] , (3) recognition of methylated H3K36 by the PCL family of proteins [107] , and (4) interactions of EZH2 and SUZ12 with transcription factors or noncoding RNA [22, 57-65, 71, 108, 109] , which may either act alone or in combination to allow PRC2 targeting to specific genomic loci [1,6] .…”

“…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] .…”

“…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] .…”