title: The epigenetic modifier ubiquitin-specific protease 22 (USP22) regulates embryonic stem cell differentiation via transcriptional repression of sex-determining region Y-box 2 (SOX2).
abstract: Pluripotent embryonic stem cells (ESCs) undergo self-renewal until stimulated to differentiate along specific lineage pathways. Many of the transcriptional networks that drive reprogramming of a self-renewing ESC to a differentiating cell have been identified. However, fundamental questions remain unanswered about the epigenetic programs that control these changes in gene expression. Here we report that the histone ubiquitin hydrolase ubiquitin-specific protease 22 (USP22) is a critical epigenetic modifier that controls this transition from self-renewal to differentiation. USP22 is induced as ESCs differentiate and is necessary for differentiation into all three germ layers. We further report that USP22 is a transcriptional repressor of the locus encoding the core pluripotency factor sex-determining region Y-box 2 (SOX2) in ESCs, and this repression is required for efficient differentiation. USP22 occupies the Sox2 promoter and hydrolyzes monoubiquitin from ubiquitylated histone H2B and blocks transcription of the Sox2 locus. Our study reveals an epigenetic mechanism that represses the core pluripotency transcriptional network in ESCs, allowing ESCs to transition from a state of self-renewal into lineage-specific differentiation programs.
authors.affiliation: Department of Cancer Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Robyn T
authors.initials: RT
authors.lastname: Sussman
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Stanek
authors.forename: Paul
authors.initials: P
authors.lastname: Esteso
authors.forename: John D
authors.initials: JD
authors.lastname: Gearhart
authors.forename: Karen E
authors.initials: KE
authors.lastname: Knudsen
authors.forename: Steven B
authors.initials: SB
authors.lastname: McMahon
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D056426:Genetic Loci / Q000235:genetics; D006657:Histones / Q000378:metabolism; D051379:Mice; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics* / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism; D014158:Transcription, Genetic; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics
chemical_list: D006657:Histones; D012333:RNA, Messenger; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D010450:Endopeptidases; C584444:USP22 protein, mouse; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Chromatin; Chromatin Histone Modification; Deubiquitylation; Embryonic Stem Cell; Epigenetics; Sox2; Stem Cells; USP22; Ubiquitin