Open AccessH3K4 Methyltransferase Set1a Is A Key Oct4 Coactivator Essential for Generation of Oct4 Positive Inner Cell Mass
Author(s) -
Fang Lan,
Zhang Jun,
Zhang Hui,
Yang Xiaoqin,
Jin Xueling,
Zhang Ling,
Skalnik David G.,
Jin Ying,
Zhang Yong,
Huang Xingxu,
Li Jiwen,
Wong Jiemin
Publication year - 2016
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.2250
Subject(s) - biology , transcription factor , klf4 , sox2 , embryonic stem cell , induced pluripotent stem cell , microbiology and biotechnology , promoter , chromatin immunoprecipitation , chromatin , stem cell , methyltransferase , genetics , gene , gene expression , methylation
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. S tem C ells 2016;34:565–580