Abstract
Identifying the critical RNA binding proteins (RBPs) that elicit Xist mediated silencing has been a key goal in X inactivation research. Early studies implicated the Polycomb proteins, a family of factors linked to one of two major multiprotein complexes, PRC1 and PRC2 (Wang 2001 Nat. Genet. 28, 371–375 (doi:10.1038/ng574); Silva 2003 Dev. Cell 4, 481–495 (doi:10.1016/S1534-5807(03)00068-6); de Napoles 2004 Dev. Cell 7, 663–676 (doi:10.1016/j.devcel.2004.10.005); Plath 2003 Science 300, 131–135 (doi:10.1126/science.1084274)). PRC1 and PRC2 complexes catalyse specific histone post-translational modifications (PTMs), ubiquitylation of histone H2A at position lysine 119 (H2AK119u1) and methylation of histone H3 at position lysine 27 (H3K27me3), respectively, and accordingly, these modifications are highly enriched over the length of the inactive X chromosome (Xi). A key study proposed that PRC2 subunits bind directly to Xist RNA A-repeat element, a region located at the 5′ end of the transcript known to be required for Xist mediated silencing (Zhao 2008 Science 322, 750–756 (doi:10.1126/science.1163045)). Subsequent recruitment of PRC1 was assumed to occur via recognition of PRC2 mediated H3K27me3 by the CBX subunit of PRC1, as has been shown to be the case at other Polycomb target loci (Cao 2002 Science 298, 1039–1043 (doi:10.1126/science.1076997)). More recently, several reports have questioned aspects of the prevailing view, both in relation to the mechanism for Polycomb recruitment by Xist RNA and the contribution of the Polycomb pathway to Xist mediated silencing. In this article I provide an overview of our recent progress towards resolving these discrepancies.This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.
Highlights
Experiments on early mouse embryos and using inducible Xist transgenes in mouse embryonic stem cells revealed that Polycomb recruitment in X inactivation is strictly dependent on ongoing Xist RNA expression [1,2]
In support of this view, conventional and super-resolution microscopy studies indicate that Xist RNA and Polycomb subunits localize closely with one another [3,4,5], a conclusion that is further supported by highthroughput chromatin immunoprecipitation based approaches that report that Polycomb occupancy on Xi correlates strongly with sites of Xist RNA binding [4,6,7,8,9,10]
Some recent variations on this theme include the suggestion that the PRC2 subunit Suz12 mediates the interaction with Xist RNA [12], that Ezh2 phosphorylation is required for efficient RNA binding [13], and more recently, that a PRC2 cofactor, Jarid2, mediates binding to Xist RNA [14], in the latter case through an element located downstream of the A-repeats
Summary
Experiments on early mouse embryos and using inducible Xist transgenes in mouse embryonic stem cells (mESCs) revealed that Polycomb recruitment in X inactivation is strictly dependent on ongoing Xist RNA expression [1,2]. It has been reported that the PRC2 subunit Ezh binds Xist RNA (or a short isoform of Xist RNA, RepA) directly, via the A-repeat, an element at the 50 end of the transcript that is critical for Xist mediated chromosome silencing [11]. This finding, based largely on in vitro interaction studies, established a model in which Polycomb recruitment to Xi is initiated. A domain in Jarid has been proposed to mediate interaction with RNA [21] but deletion of this region has no effect on PRC2 recruitment by Xist RNA [14]
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