An Orthologous Epigenetic Gene Expression Signature Derived from Differentiating Embryonic Stem Cells Identifies Regulators of Cardiogenesis.
Here we used predictive gene expression signatures within a multi-species framework to identify the genes that underlie cardiac cell fate decisions in differentiating embryonic stem cells. We show that the overlapping orthologous mouse and human genes are the most accurate candidate cardiogenic genes as these genes identified the most conserved developmental pathways that characterize the cardiac lineage. An RNAi-based screen of the candidate genes in Drosophila uncovered numerous novel cardiogenic genes. shRNA knockdown combined with transcriptome profiling of the newly-identified transcription factors zinc finger protein 503 and zinc finger E-box binding homeobox 2 and the well-known cardiac regulatory factor NK2 homeobox 5 revealed that zinc finger E-box binding homeobox 2 activates terminal differentiation genes required for cardiomyocyte structure and function whereas zinc finger protein 503 and NK2 homeobox 5 are required for specification of the cardiac lineage. We further demonstrated that an essential role of NK2 homeobox 5 and zinc finger protein 503 in specification of the cardiac lineage is the repression of gene expression programs characteristic of alternative cell fates. Collectively, these results show that orthologous gene expression signatures can be used to identify conserved cardiogenic pathways.
Systems Biology Center, Division of Intramural Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America.
Brian W
BW
Busser
Center for Molecular Medicine, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America.
Yongshun
Y
Lin
Systems Biology Center, Division of Intramural Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America.
Yanqin
Y
Yang
Systems Biology Center, Division of Intramural Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America.
Jun
J
Zhu
Center for Molecular Medicine, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America.
Guokai
G
Chen
Systems Biology Center, Division of Intramural Research, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, United States of America.
Alan M
AM
Michelson
D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D004330:Drosophila / Q000196:embryology / Q000235:genetics* / Q000254:growth & development; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D057890:Epigenomics; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D038081:Organogenesis / Q000235:genetics*; D034622:RNA Interference / Q000502:physiology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics
D015415:Biomarkers; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D014157:Transcription Factors