Cited2 gene controls pluripotency and cardiomyocyte differentiation of murine embryonic stem cells through Oct4 gene

J Biol Chem. 2012 Aug 17;287(34):29088-100. doi: 10.1074/jbc.M112.378034. Epub 2012 Jul 3.


Cited2 (CBP/p300-interacting transactivator with glutamic acid (E)/aspartic acid (D)-rich tail 2) is a transcriptional modulator critical for the development of multiple organs. Although many Cited2-mediated phenotypes and molecular events have been well characterized using in vivo genetic murine models, Cited2-directed cell fate decision in embryonic stem cells (ESCs) remains elusive. In this study, we examined the role of Cited2 in the maintenance of stemness and pluripotency of murine ESCs by a gene-targeting approach. Cited2 knock-out (Cited2(Δ/-), KO) ESCs display defective differentiation. Loss of Cited2 in differentiating ESCs results in delayed silencing of the genes involved in the maintenance of pluripotency and self-renewal of stem cells (Oct4, Klf4, Sox2, and c-Myc) and the disturbance in cardiomyocyte, hematopoietic, and neuronal differentiation. In addition, Cited2 KO ESCs experience a delayed induction of cardiomyocyte differentiation-associated proteins, NFAT3 (along with the reduced expression of NFAT3 target genes, Nkx2.5 and β-MHC), N-cadherin, and smooth muscle actin. CITED2 is recruited to the Oct4 promoter to regulate its expression during early ESC differentiation. This is the first demonstration that Cited2 controls ESC pluripotency and differentiation via direct regulation of Oct4 gene expression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / biosynthesis
  • Actins / genetics
  • Animals
  • Cadherins / biosynthesis
  • Cadherins / genetics
  • Cell Differentiation / physiology*
  • Cells, Cultured
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism*
  • Gene Expression Regulation / physiology
  • Gene Knockdown Techniques
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins / biosynthesis
  • Homeodomain Proteins / genetics
  • Kruppel-Like Transcription Factors / biosynthesis
  • Kruppel-Like Transcription Factors / genetics
  • Mice
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism*
  • NFATC Transcription Factors / biosynthesis
  • NFATC Transcription Factors / genetics
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism*
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism*
  • Proto-Oncogene Proteins c-myc / biosynthesis
  • Proto-Oncogene Proteins c-myc / genetics
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • SOXB1 Transcription Factors / biosynthesis
  • SOXB1 Transcription Factors / genetics
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics


  • Actins
  • Cadherins
  • Cdh2 protein, mouse
  • Cited2 protein, mouse
  • GKLF protein
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins
  • Kruppel-Like Transcription Factors
  • Myc protein, mouse
  • NFATC Transcription Factors
  • Nkx2-5 protein, mouse
  • Octamer Transcription Factor-3
  • Pou5f1 protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Repressor Proteins
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse
  • Trans-Activators
  • Transcription Factors