Abstract
SummaryThrough the histone methyltransferase EZH2, the Polycomb complex PRC2 mediates H3K27me3 and is associated with transcriptional repression. PRC2 regulates cell-fate decisions in model organisms; however, its role in regulating cell differentiation during human embryogenesis is unknown. Here, we report the characterization of EZH2-deficient human embryonic stem cells (hESCs). H3K27me3 was lost upon EZH2 deletion, identifying an essential requirement for EZH2 in methylating H3K27 in hESCs, in contrast to its non-essential role in mouse ESCs. Developmental regulators were derepressed in EZH2-deficient hESCs, and single-cell analysis revealed an unexpected acquisition of lineage-restricted transcriptional programs. EZH2-deficient hESCs show strongly reduced self-renewal and proliferation, thereby identifying a more severe phenotype compared to mouse ESCs. EZH2-deficient hESCs can initiate differentiation toward developmental lineages; however, they cannot fully differentiate into mature specialized tissues. Thus, EZH2 is required for stable ESC self-renewal, regulation of transcriptional programs, and for late-stage differentiation in this model of early human development.
Highlights
Polycomb-group (PcG) proteins are epigenetic repressors of transcriptional programs and maintain cellular identity during development, differentiation, and disease (Di Croce and Helin, 2013; Pasini and Di Croce, 2016; Pietersen and van Lohuizen, 2008; Schuettengruber and Cavalli, 2009; Surface et al, 2010)
Our findings demonstrate that EZH2 is required to maintain the transcriptional repression of developmental regulators and for cells to undergo late-stage cell differentiation, thereby revealing the broad conservation of PRC2 function in this model of early human development
We identify unexpected human-specific differences such as the essential requirement in human embryonic stem cells (hESCs) for EZH2 to maintain PRC2 stability and retain promoter-localized H3K27me3, which is in contrast to its nonessential role in mouse embryonic stem cells (ESCs)
Summary
Polycomb-group (PcG) proteins are epigenetic repressors of transcriptional programs and maintain cellular identity during development, differentiation, and disease (Di Croce and Helin, 2013; Pasini and Di Croce, 2016; Pietersen and van Lohuizen, 2008; Schuettengruber and Cavalli, 2009; Surface et al, 2010). PRC1 catalyzes histone H2A lysine 119 ubiquitination through the activity of the E3 ligases RING1A and RING1B (Mu€ller and Verrijzer, 2009; Wang et al, 2004). PRC2 is composed of the core proteins EZH2, EED, and SUZ12, together with RBAP46/48 and several other accessory subunits, and is responsible for catalyzing di- and trimethylation on histone H3 lysine 27 (H3K27me2/3) (Cao et al, 2002; Czermin et al, 2002; Kuzmichev et al, 2002; Margueron and Reinberg, 2011; Mu€ller et al, 2002). EED and SUZ12 are required for substrate recognition, complex stability and for promoting the enzymatic activity of EZH2 (Cao and Zhang, 2004; Nekrasov et al, 2005; Pasini et al, 2004; Tie et al, 2007)
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