Essential and Unexpected Role of YY1 to Promote Mesodermal Cardiac Differentiation

1Massachusetts General Hospital, Massachusetts, UNITED STATES.
Circulation Research (Impact Factor: 11.02). 03/2013; 112(6). DOI: 10.1161/CIRCRESAHA.113.259259


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).

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.

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.

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    • "YY1 is crucial for embryonic development because homozygous mutation of the yy1 gene in mice results in peri-implantation lethality (18). YY1 is implicated in lineage differentiation of skeletal and cardiac muscle, and in cell growth control (13, 17, 19–24), as well as disease pathways such as dystrophic muscle disease (25–27). YY1 and its target genes are also believed to be central regulators of germinal center B cell development (28), and YY1 has been suggested to regulate genomic targeting of activation induced cytidine deaminase (AID) (29). "
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    • "ANRIL belongs to the group of large noncoding RNAs which have been shown to regulate gene expression through RNA–RNA, RNA–DNA, or RNA–protein interactions [68–70]. For ANRIL, binding to epigenetic silencer Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) [59▪,66,67] and to PRC-associated activating proteins RYBP and YY1 [71,72] has been demonstrated (Fig. 3) [59▪]. In accordance, modulation of ANRIL expression led to the epigenetic regulation of target genes expression in cis[66,67] and in trans[59▪,64,73]. "
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