ISL1 and JMJD3 synergistically control cardiac differentiation of embryonic stem cells.
ISL1 is expressed in cardiac progenitor cells and plays critical roles in cardiac lineage differentiation and heart development. Cardiac progenitor cells hold great potential for clinical and translational applications. However, the mechanisms underlying ISL1 function in cardiac progenitor cells have not been fully elucidated. Here we uncover a hierarchical role of ISL1 in cardiac progenitor cells, showing that ISL1 directly regulates hundreds of potential downstream target genes that are implicated in cardiac differentiation, through an epigenetic mechanism. Specifically, ISL1 promotes the demethylation of tri-methylation of histone H3K27 (H3K27me3) at the enhancers of key downstream target genes, including Myocd and Mef2c, which are core cardiac transcription factors. ISL1 physically interacts with JMJD3, a H3K27me3 demethylase, and conditional depletion of JMJD3 leads to impaired cardiac progenitor cell differentiation, phenocopying that of ISL1 depletion. Interestingly, ISL1 is not only responsible for the recruitment of JMJD3 to specific target loci during cardiac progenitor differentiation, but also modulates its demethylase activity. In conclusion, ISL1 and JMJD3 partner to alter the cardiac epigenome, instructing gene expression changes that drive cardiac differentiation.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China; Peking University, Beijing 100191, PR China.
Yang
Y
Wang
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China; Peking University, Beijing 100191, PR China.
Yuejiao
Y
Li
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China; Peking University, Beijing 100191, PR China.
Chen
C
Guo
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China; Peking University, Beijing 100191, PR China.
Qin
Q
Lu
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China; Peking University, Beijing 100191, PR China.
Weiping
W
Wang
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China; Peking University, Beijing 100191, PR China.
Zhuqing
Z
Jia
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China; Peking University, Beijing 100191, PR China.
Ping
P
Chen
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China; Peking University, Beijing 100191, PR China.
Kangtao
K
Ma
Howard Hughes Medical Institute, New York University Langone School of Medicine, Department of Biochemistry and Molecular Pharmacology, New York, NY 10016, USA.
Danny
D
Reinberg
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences; Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China; Peking University, Beijing 100191, PR China chunyanzhou@bjmu.edu.cn.
Chunyan
C
Zhou
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D016678:Genome; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology*; D041681:NIH 3T3 Cells; D009928:Organ Specificity; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D006657:Histones; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse; D008239:Lysine