Jarid2 Is Implicated in the Initial Xist-Induced Targeting of PRC2 to the Inactive X Chromosome

Abstract

During X chromosome inactivation (XCI), the Polycomb Repressive Complex 2 (PRC2) is thought to participate in the early maintenance of the inactive state. Although Xist RNA is essential for the recruitment of PRC2 to the X chromosome, the precise mechanism remains unclear. Here, we demonstrate that the PRC2 cofactor Jarid2 is an important mediator of Xist-induced PRC2 targeting. The region containing the conserved B and F repeats of Xist is critical for Jarid2 recruitment via its unique N-terminal domain. Xist-induced Jarid2 recruitment occurs chromosome-wide independently of a functional PRC2 complex, unlike at other parts of the genome, such as CG-rich regions, where Jarid2 and PRC2 binding are interdependent. Conversely, we show that Jarid2 loss prevents efficient PRC2 and H3K27me3 enrichment to Xist-coated chromatin. Jarid2 thus represents an important intermediate between PRC2 and Xist RNA for the initial targeting of the PRC2 complex to the X chromosome during onset of XCI.

The recruitment of chromatin modifiers by long noncoding RNAs: lessons from PRC2

“…2C) or by the aid of a bridging protein such as JARID2 ( Fig. 2D; da Rocha et al 2014;Kaneko et al 2014a,b). Upon recruitment, PRC2 deposits the H3K27me3 mark that leads to repression.…”

“…(C) Direct and specific interactions with lncRNAs: Site-specific recruitment of PRC2 could occur in cis or in trans (references in text). (D) Bridging and remodeling: Recruitment of PRC2 by RNA can be mediated through protein bridging factors, such as JARID2 (da Rocha et al 2014;Kaneko et al 2014a,b), or through RNA structure remodeling, as suggested for ATRX . (E) Masking: PRC2 is masked from binding to certain RNA transcripts that are already bound by other factors, thus providing a binding preference (Herzog et al 2014).…”

The RIDL hypothesis: transposable elements as functional domains of long noncoding RNAs

“…This region also has a repetitive origin, having homology to another endogenous retrovirus, ERVB4 (Elisaphenko et al 2008). Most recently, it was shown that the conserved Repeat F is part of the core region necessary for Jarid2 interaction and may have originated from a DNA transposon (Elisaphenko et al 2008;da Rocha et al 2014). Thus, the distinct functionalities of XIST, targeting and silencing, appear to have evolved from transposable elements, which in combination give XIST at least three distinct protein-binding modules as depicted in Figure 3B.…”

Structure of the PRC2 complex and application to drug discovery

“…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] .…”

“…For instance, PRC2 and H3K27me3 accumulate on the inactive X chromosome during X inactivation. Subsequently, it was shown that the key regulator of X inactivation, the lncRNA Xist, can interact with PRC2 through the PRC2-cofactor JARID2 [34,60] . HOTAIR is a lncRNA that recruits PRC2 to the HOXD locus101 [68] , whereas the lncRNA Kcnqot1 is involved in imprinting the Kcnq1 cluster in a process that requires PRC2 [69] .…”