PRC2 Facilitates the Regulatory Topology Required for Poised Enhancer Function during Pluripotent Stem Cell Differentiation

Abstract

Highlights d Poised enhancers are necessary for the induction of major anterior neural genes d Poised enhancers physically contact their target genes in embryonic stem cells d The interaction between poised enhancers and their target genes is PRC2 dependent d PRC2 provides major anterior neural loci with a permissive regulatory topology

Switch-Like Roles for Polycomb Proteins from Neurodevelopment to Neurodegeneration

“…Thereby, PcG dependent interactions may form 3D chromatin hubs that coordinate repression and the activation of early (neuro-) developmental regulators ( Figure 3). Beyond preventing precocious activation of early neural genes, PcG proteins can also preset future activation of major anterior neural genes once the differentiation signal has been received [12]. In this scenario, PcG proteins endow poised enhancers with a permissive regulatory topology that enables pluripotent cells to respond effectively to neural induction signals (Figure 4).…”

“…domains form and resolve dynamically during successive neurodevelopmental stages to regulate diverse sets of target genes. Moving beyond the linear chromatin landscape, most recently Cruz-Molina et al [12] showed that PRC2 mediated contacts with poised enhancers (see Section 4.1) and promoters in ESCs established a permissive environment that preconditioned the induction of major anterior neural genes (e.g., Lhx5, Six3, Sox1, Wnt8b, Sox21) in NPCs. Genome-wide mapping of EP300 and H3K27me3 detected ≈1000 poised enhancers that were enriched in genes that were necessary for the development of the anterior neural tube.…”

“…In addition to this rigid role, recent findings show that PcG proteins are also involved in the dynamic and recurrent "On-Off" switches in gene regulatory activity [11] that contribute to distinct cell lineage decisions and the nascence of highly diverse cell types [10,[12][13][14]. These regulatory transitions are guided by molecular epigenetic mechanisms that elsewise sustain a memory of cellular identity throughout development [3,15,16].…”

Thrombopoietin signaling to chromatin elicits rapid and pervasive epigenome remodeling within poised chromatin architectures

“…Cold Spring Harbor Laboratory Press on May 9, 2018 -Published by genome.cshlp.org Downloaded from Collectively, studies in different systems across multiple species using 3C-based methods and derivatives identified two types of enhancer-promoter interactions: loops formed de novo and pre-existing loops (Melo et al 2013;Eijkelenboom et al 2014;Freire-Pritchett et al 2017;Montavon et al 2011;Ghavi-Helm et al 2014;Apostolou et al 2013;Cruz-Molina et al 2017). While de novo (also called instructive) interactions appear concomitant with changes in the target gene activity, pre-existing (also called permissive) interactions are formed prior to gene activation and are thought to facilitate timely transcriptional induction (de Laat and Duboule 2013;Bouwman and de Laat 2015).…”

Multitasking by Polycomb response elements

“…For example, both activation by enhancers and repression by the PcG proteins are known to involve higher-order interactions that place distant regions adjacent to one another by either looping or forming discrete domains of interaction (Deng et al 2012;Williamson et al 2012;Kundu et al 2017). There have been suggestions that PcG-mediated looping might help with driving activating interactions (Cruz-Molina et al 2017). Another area of mechanistic overlap involves the necessity of altering chromatin structure to facilitate binding by the full complement of factors that are needed to generate a PRE or an enhancer.…”