title: Essential and unexpected role of Yin Yang 1 to promote mesodermal cardiac differentiation.
abstract: BACKGROUND
  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.
  
  
  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.
authors: Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA (
authors: Serge
authors: S
authors: Gregoire
authors: Ravi
authors: R
authors: Karra
authors: Derek
authors: D
authors: Passer
authors: Marcus-André
authors: MA
authors: Deutsch
authors: Markus
authors: M
authors: Krane
authors: Rebecca
authors: R
authors: Feistritzer
authors: Anthony
authors: A
authors: Sturzu
authors: Ibrahim
authors: I
authors: Domian
authors: Yumiko
authors: Y
authors: Saga
authors: Sean M
authors: SM
authors: Wu
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000166:cytology*; D050991:GATA4 Transcription Factor / Q000378:metabolism; D055106:Genome-Wide Association Study / Q000379:methods; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism*; D051379:Mice; D032386:Myoblasts, Cardiac / Q000737:chemistry / Q000166:cytology*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology; D050986:YY1 Transcription Factor / Q000032:analysis / Q000235:genetics / Q000502:physiology*
chemical_list: D050991:GATA4 Transcription Factor; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494699:Yy1 protein, mouse