title: A methylation-phosphorylation switch determines Sox2 stability and function in ESC maintenance or differentiation.
abstract: Sox2 is a key factor for maintaining embryonic stem cell (ESS) pluripotency, but little is known about its posttranslational regulation. Here we present evidence that the precise level of Sox2 proteins in ESCs is regulated by a balanced methylation and phosphorylation switch. Set7 monomethylates Sox2 at K119, which inhibits Sox2 transcriptional activity and induces Sox2 ubiquitination and degradation. The E3 ligase WWP2 specifically interacts with K119-methylated Sox2 through its HECT domain to promote Sox2 ubiquitination. In contrast, AKT1 phosphorylates Sox2 at T118 and stabilizes Sox2 by antagonizing K119me by Set7 and vice versa. In mouse ESCs, AKT1 activity toward Sox2 is greater than that of Set7, leading to Sox2 stabilization and ESC maintenance. In early development, increased Set7 expression correlates with Sox2 downregulation and appropriate differentiation. Our study highlights the importance of a Sox2 methylation-phosphorylation switch in determining ESC fate.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Fang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Xueling
authors.initials: X
authors.lastname: Jin
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Tong
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Jiwen
authors.initials: J
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: James X
authors.initials: JX
authors.lastname: Du
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China. Electronic address: jmweng@bio.ecnu.edu.cn.
authors.forename: Jiemin
authors.initials: J
authors.lastname: Wong
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D019175:DNA Methylation / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000502:physiology*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation / Q000502:physiology*; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D013941:Thymine / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism / Q000502:physiology*; D054875:Ubiquitination
chemical_list: D055748:SOXB1 Transcription Factors; D011495:Histone-Lysine N-Methyltransferase; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt; D008239:Lysine; D013941:Thymine