Coordinate redeployment of PRC1 proteins suppresses tumor formation during Drosophila development

Abstract

Polycomb group proteins form two main complexes, PRC2 and PRC1, which generally coregulate their target genes. Here, we show that PRC1 components act as neoplastic tumor suppressors independently of PRC2 function. By mapping the distribution of PRC1 components and the histone H3K27me3 mark, we identify a large set of genes that acquire PRC1 in the absence of H3K27me3 in Drosophila larval tissues. These genes massively outnumber canonical targets and they are preeminently involved in the regulation of cell proliferation, signaling and polarity. Mutation in PRC1 components specifically deregulates this set of genes, whereas canonical targets are derepressed in both PRC1 and PRC2 mutants. In human ES cells, PRC1 components colocalize with H3K27me3 like in Drosophila embryos, whereas in differentiated cell types they are selectively recruited to a large set of proliferation and signaling-associated genes that are H3K27me3 negative, showing that the redeployment of PRC1 components during development is evolutionarily conserved.Polycomb group (PcG) proteins form two main classes of evolutionarily conserved complexes called PRC2 and PRC1. In Drosophila, PRC2 contains the enzymatic E(Z) subunit that deposits the H3K27me3 mark, along with SU(Z)12, ESC and p55 1-4. A second class of PcG complex, PRC1, was shown to contain PH, PC, PSC and the SCE subunits 5. These two complexes are recruited to their target sites by a set of DNA binding proteins, notably PHO 6. They colocalize almost perfectly in embryogenesis7, and their Correspondence to: Anne-Marie.Martinez@igh.cnrs.fr and Giacomo.Cavalli@igh.cnrs.fr. Accession codes Drosophila ChIP-Seq and RNA-Seq data are deposited to the Gene Expression Omnibus (GEO) repository under the accession number GSE74080.

Three-Dimensional Genome Organization and Function in Drosophila

“…Although many of the targets are consistently found in all cell types, other targets are dynamically bound and regulated, such as the Notch gene, which is bound and repressed by the PH component of PRC1 in larval development but not in embryos (Martinez et al 2009). Indeed a recent study has shown that PcG binding is dynamic during development and that two types of PcG target genes exist: canonical targets carrying PRC1 and PRC2 binding in the presence of the H3K27me3 mark, and a novel category, defined as neo-PRC1 genes, which include the Notch gene and are bound by PRC1 and PRC2 in the absence of its H3K27me3 mark (Loubiere et al 2016). …”

Maintenance of spatial gene expression by Polycomb-mediated repression after formation of a vertebrate body plan

“…PRC1 catalyzes the ubiquitination of lysine 119 of histone H2A (H2AK1119ub) and strengthens gene repression. In contrast to this canonical view, recent studies implicate that PRC1 is also active in the absence of PRC2 (He et al, 2013, Loubiere et al, 2016, Tavares et al, 2012). Trithorax Group (TrxG) proteins antagonize PcG protein function through the deposition of a trimethyl group on lysine 4 of histone H3 (H3K4me3) on promoters and enhancers from virtually all transcribed genes (Klymenko and Muller, 2004, Schmitges et al, 2011, Santos-Rosa et al, 2002).…”

The regulatory function of dIno80 correlates with its DNA binding activity

“…Kwong et al [46] have identified many variable binding sites for Pho in the Drosophila genome, which partially overlap with Polycomb binding sites. Loubiere et al [47] have shown the presence of weaker Pho binding sites which are associated with transcriptional activation mediated by PRC1complex exclusively. The binding of Pho and dIno80 independent of each other is reflected in the detection of exclusive motif for Pho and also dIno80 binding, in addition to shared sites.…”