Histone H2A Mono-Ubiquitination Is a Crucial Step to Mediate PRC1-Dependent Repression of Developmental Genes to Maintain ES Cell Identity

Abstract

Two distinct Polycomb complexes, PRC1 and PRC2, collaborate to maintain epigenetic repression of key developmental loci in embryonic stem cells (ESCs). PRC1 and PRC2 have histone modifying activities, catalyzing mono-ubiquitination of histone H2A (H2AK119u1) and trimethylation of H3 lysine 27 (H3K27me3), respectively. Compared to H3K27me3, localization and the role of H2AK119u1 are not fully understood in ESCs. Here we present genome-wide H2AK119u1 maps in ESCs and identify a group of genes at which H2AK119u1 is deposited in a Ring1-dependent manner. These genes are a distinctive subset of genes with H3K27me3 enrichment and are the central targets of Polycomb silencing that are required to maintain ESC identity. We further show that the H2A ubiquitination activity of PRC1 is dispensable for its target binding and its activity to compact chromatin at Hox loci, but is indispensable for efficient repression of target genes and thereby ESC maintenance. These data demonstrate that multiple effector mechanisms including H2A ubiquitination and chromatin compaction combine to mediate PRC1-dependent repression of genes that are crucial for the maintenance of ESC identity. Utilization of these diverse effector mechanisms might provide a means to maintain a repressive state that is robust yet highly responsive to developmental cues during ES cell self-renewal and differentiation.

USP7 Cooperates with SCML2 To Regulate the Activity of PRC1

“…There are different versions of PRC1 in mammals, and they mediate the monoubiquitination of histone H2A at lysine 119 (H2Aub), a modification associated with transcriptionally repressed chromatin (14). The different species of PRC1 share an E3 ubiquitin protein ligase, RING1B.…”

CBX7 inhibits breast tumorigenicity through DKK‐1‐mediated suppression of the Wnt/β‐catenin pathway

“…The FASEB Journal x www.fasebj.org involved in the regulation of both normal stem cells and CSCs (35). Moreover, the enzymatic activities of PcG members toward histones were reported to be essential for maintaining the self-renewal of embryonic and adult stem cells as well as CSCs (36)(37)(38). Although CBX proteins are crucial for linking PRC-2 and PRC-1 activities, few studies have reported their role in stemness.…”

BMI1–RING1B is an autoinhibited RING E3 ubiquitin ligase

“…The importance of H2A K119ub in PRC1-enforced gene repression has been studied in several systems [11][12][13] (reviewed in refs 14,15). Introduction of a catalytically inactive RING1B mutant into Ring1A À / À Ring1B conditional knockout embryonic stem (ES) cells 12 established that H2A ubiquitination is dispensable for chromatin compaction but essential for maintaining repression of target genes and for maintaining ES cells in a dedifferentiated state. Although some details of PRC1 function are different in Drosophila 15 , it appears that H2A ubiquitination is again critical for a subset of PRC1 function 13 .…”