title: H3K4 Methyltransferase Set1a Is A Key Oct4 Coactivator Essential for Generation of Oct4 Positive Inner Cell Mass.
abstract: Limited core transcription factors and transcriptional cofactors have been shown to govern embryonic stem cell (ESC) transcriptional circuitry and pluripotency, but the molecular interactions between the core transcription factors and cofactors remains ill defined. Here, we analyzed the protein-protein interactions between Oct4, Sox2, Klf4, and Myc (abbreviated as OSKM) and a large panel of cofactors. The data reveal both specific and common interactions between OSKM and cofactors. We found that among the SET1/MLL family H3K4 methyltransferases, Set1a specifically interacts with Oct4 and this interaction is independent of Wdr5. Set1a is recruited to and required for H3K4 methylation at the Oct4 target gene promoters and transcriptional activation of Oct4 target genes in ESCs, and consistently Set1a is required for ESC maintenance and induced pluripotent stem cell generation. Gene expression profiling and chromatin immunoprecipitation-seq analyses demonstrate the broad involvement of Set1a in Oct4 transcription circuitry and strong enrichment at TSS sites. Gene knockout study demonstrates that Set1a is not only required for mouse early embryonic development but also for the generation of Oct4-positive inner cell mass. Together our study provides valuable information on the molecular interactions between OSKM and cofactors and molecular mechanisms for the functional importance of Set1a in ESCs and early development.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Fang
authors.affiliation: MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University and National Resource Center for Mutant Mice, Nanjing, China.|School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
authors.forename: Jun
authors.initials: J
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, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, China.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Yang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 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, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Biology Department, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Skalnik
authors.affiliation: Department of Molecular Development, Shanghai JiaoTong University School of Medicine, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University and National Resource Center for Mutant Mice, Nanjing, China.|School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
authors.forename: Xingxu
authors.initials: X
authors.lastname: Huang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 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, China.|Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Jiemin
authors.initials: J
authors.lastname: Wong
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D053624:Blastocyst Inner Cell Mass / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D053263:Gene Regulatory Networks; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000378:metabolism* / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000235:genetics* / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000378:metabolism; D011401:Promoter Regions, Genetic; D060066:Protein Interaction Maps / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase
keywords: Embryonic stem cells; Epigenetics; Induced pluripotent stem cells; Targeted gene disruption; Transcription factors