title: Deletion of the Polycomb-Group Protein EZH2 Leads to Compromised Self-Renewal and Differentiation Defects in Human Embryonic Stem Cells.
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.
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Collinson
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK; Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Collier
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Natasha P
authors.initials: NP
authors.lastname: Morgan
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Arnold R
authors.initials: AR
authors.lastname: Sienerth
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Tamir
authors.initials: T
authors.lastname: Chandra
authors.affiliation: Bioinformatics Group, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Andrews
authors.affiliation: 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.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Rugg-Gunn
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D000066673:Cell Self Renewal / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics*; D000066449:Human Embryonic Stem Cells / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics; D051379:Mice; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D063146:Polycomb-Group Proteins / Q000235:genetics; D017384:Sequence Deletion; D059010:Single-Cell Analysis
chemical_list: D063146:Polycomb-Group Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: differentiation; epigenetics; histone methylation; pluripotency