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Cell Rep. 2016 Dec 6;17(10):2700-2714. doi: 10.1016/j.celrep.2016.11.032.

Deletion of the Polycomb-Group Protein EZH2 Leads to Compromised Self-Renewal and Differentiation Defects in Human Embryonic Stem Cells.

Author information

1
Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
2
Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK; Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK.
3
Bioinformatics Group, The Babraham Institute, Cambridge CB22 3AT, UK.
4
Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK; Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK. Electronic address: peter.rugg-gunn@babraham.ac.uk.

Abstract

Through 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.

KEYWORDS:

differentiation; epigenetics; histone methylation; pluripotency

PMID:
27926872
PMCID:
PMC5177603
DOI:
10.1016/j.celrep.2016.11.032
[Indexed for MEDLINE]
Free PMC Article

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