A temporal transcriptome and methylome in human embryonic stem cell-derived cardiomyocytes identifies novel regulators of early cardiac development
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PROVIDER: PRJNA493552 | ENA |
REPOSITORIES: ENA
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Project description:Stem cell-based cardiogenesis has become a powerful tool to enhance our understanding of cardiac development and test novel therapeutics for cardiovascular diseases. However, transcriptional and epigenetic regulation of multiple transitional stages from pluripotent cells to committed cardiomyocytes has not yet been fully characterized. To characterize how transcription factors, lincRNAs and DNA methylation change at temporal developmental stages, and identify potential novel regulators during cardiogenesis. We utilized a previously reported protocol that yields human cardiomyocytes (hCM) with more than 90% purity from human Embryonic Stem Cells (hESC). Leveraging the purity of cells resulting from this protocol, we systematically examined how gene expression and DNA methylation programs change at temporal developmental stages during cardiogenesis. Our results provide a comprehensive view of expression changes during cardiogenesis that extend previous studies, allowing us to identify key transcription factors as well as lincRNAs that are strongly associated with cardiac differentiation. Moreover, we incorporated a simple but powerful method to screen for novel regulators of cardiogenesis solely based on expression changes and found four novel cardiac-related transcription factors, i.e., SORBS2, MITF, DPF3, and ZNF436, which have no or few prior literature reports and we were able to validate using siRNA. Our strategy of identifying novel regulators of cardiogenesis can also be easily implemented in other stem cell-based systems. Our results provide a valuable resource for understanding cardiogenesis that extends previous findings by leveraging the purity of our cell lines, which allowed us to identify four novel cardiac-related regulators.
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Project description:During development the fetal heart undergoes a rapid and dramatic transition to adult function through transcriptional and post-transcriptional mechanisms, including alternative splicing (AS). We performed deep RNA-sequencing for high-resolution analysis of transcriptome changes during postnatal mouse heart development using RNA from ventricles and freshly isolated cardiomyocytes (CM) and cardiac fibroblasts (CF). Extensive changes in gene expression and AS occur primarily between postnatal days 1 and 28. CM and CF showed reciprocal regulation of gene expression during postnatal development reflecting differences in proliferative capacity, cell adhesion functions, and mitochondrial metabolism. We found that AS plays a novel role in vesicular trafficking and membrane organization during postnatal CM development. Interestingly, these AS transitions are enriched among targets of two RNA-binding proteins, Celf1 and Mbnl1, which undergo developmentally regulated change in expression. Vesicular traffic genes affected by AS during normal development where Celf1 is down-regulated, showed a reversion to neonatal AS patterns when Celf1 was over-expressed in adults. RNA-seq was performed in RNA samples of ventricles, cardiomyocytes or cardiac fibroblast at different developmental stages; embryonic day 17, postnatal day (PN) 1, 10, 28 and 90 for ventricles, PN1-3, PN28 and PN60 for cardiac fibroblasts, and PN1-2, PN30, and PN67 for cardiomyocytes
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