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Keywords:

  • Embryonic stem cells;
  • Pluripotency;
  • Differentiation;
  • Progenitor cells;
  • Cardiac myocytes

Abstract

Oct4 is the gatekeeper of stem cell pluripotency, but recent evidences also support Oct4 as a key regulator of germ layer formation and lineage commitment. How Oct4 contributes to lineage commitment is not well understood. We identified a Tcf/Lef-Oct4 composite site in the promoter of the cardiac mesoderm gene Mesp1, with a nucleotide sequence identical to the previously established Sox2-Oct4 composite site. This Tcf/Lef-Oct4 composite site mediated synergistic activation of the Mesp1 promoter by Oct4 and canonical Wnt signaling. Transcription ternary complexes were formed with Oct4 and Wnt terminal components, Lef1. Point mutations on the Tcf/Lef-Oct4 composite site impaired Oct4 and Lef1 binding and Mesp1-β-gal transgene reporter expression during mouse embryogenesis. In ZHBTc4 murine embryonic stem cells, the loss of Oct4 during differentiation impaired Mesp1 expression and the development of the cardiac program. This Tcf/Lef-Oct4 composite site appears to be a unique nodal point regulatory element that may drive pluripotency via Sox2-Oct4 and switch on lineage-related genes through Oct4's recruitment of Tcf/Lef factors. STEM Cells 2013;31:1213–1217