Essential and unexpected role of Yin Yang 1 to promote mesodermal cardiac differentiation.
RATIONALE: Cardiogenesis is regulated by a complex interplay between transcription factors. However, little is known about how these interactions regulate the transition from mesodermal precursors to cardiac progenitor cells (CPCs). OBJECTIVE: To identify novel regulators of mesodermal cardiac lineage commitment. METHODS AND RESULTS: We performed a bioinformatic-based transcription factor binding site analysis on upstream promoter regions of genes that are enriched in embryonic stem cell-derived CPCs. From 32 candidate transcription factors screened, we found that Yin Yang 1 (YY1), a repressor of sarcomeric gene expression, is present in CPCs in vivo. Interestingly, we uncovered the ability of YY1 to transcriptionally activate Nkx2.5, a key marker of early cardiogenic commitment. YY1 regulates Nkx2.5 expression via a 2.1-kb cardiac-specific enhancer as demonstrated by in vitro luciferase-based assays, in vivo chromatin immunoprecipitation, and genome-wide sequencing analysis. Furthermore, the ability of YY1 to activate Nkx2.5 expression depends on its cooperative interaction with Gata4 at a nearby chromatin. Cardiac mesoderm-specific loss-of-function of YY1 resulted in early embryonic lethality. This was corroborated in vitro by embryonic stem cell-based assays in which we showed that the overexpression of YY1 enhanced the cardiogenic differentiation of embryonic stem cells into CPCs. CONCLUSIONS: These results demonstrate an essential and unexpected role for YY1 to promote cardiogenesis as a transcriptional activator of Nkx2.5 and other CPC-enriched genes.
Duke Scholars
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- YY1 Transcription Factor
- Transcriptional Activation
- Transcription Factors
- Myoblasts, Cardiac
- Mice
- Homeodomain Proteins
- Homeobox Protein Nkx-2.5
- Genome-Wide Association Study
- GATA4 Transcription Factor
- Embryonic Stem Cells
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- YY1 Transcription Factor
- Transcriptional Activation
- Transcription Factors
- Myoblasts, Cardiac
- Mice
- Homeodomain Proteins
- Homeobox Protein Nkx-2.5
- Genome-Wide Association Study
- GATA4 Transcription Factor
- Embryonic Stem Cells