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Tcf15 primes pluripotent cells for differentiation

Owen R Davies1, Chia-Yi Lin, Aliaksandra Radzisheuskaya

  • 1Institute for Stem Cell Research, MRC Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh EH16 4UU, UK.

Cell Reports
|February 12, 2013
PubMed

Insights

Inhibitor of DNA binding/differentiation (Id) proteins regulate pluripotency. Tcf15, an Id-regulated factor, primes embryonic stem cells for differentiation by downregulating Nanog, especially with fibroblast growth factor (FGF) signaling.

Area of Science:

  • Stem cell biology
  • Developmental biology
  • Molecular genetics

Background:

  • Pluripotent stem cells must be primed for differentiation, but the underlying molecular events remain unclear.
  • Inhibitor of DNA binding/differentiation (Id) proteins maintain pluripotency by inhibiting basic helix-loop-helix (bHLH) transcription factors.
  • Understanding factors that control the transition from pluripotency to differentiation is crucial for developmental studies.

Purpose of the Study:

  • To identify Id-regulated transcription factors involved in embryonic stem cell (ESC) pluripotency and differentiation.
  • To investigate the role of Tcf15 in priming ESCs for somatic lineage commitment.
  • To elucidate the connection between fibroblast growth factor (FGF) signaling and differentiation priming.

Main Methods:

  • Yeast-two-hybrid screens to identify Id-interacting proteins in ESCs.
  • Expression analysis of identified factors in ESCs and early embryos.
  • Functional studies using an Id-resistant Tcf15 mutant to assess effects on Nanog and lineage commitment.
  • Investigation of Tcf15 expression dependency on FGF signaling.

Main Results:

  • Identification of Tcf15 as an Id-regulated transcription factor expressed in ESCs and the early embryo.
  • Tcf15 is associated with a distinct subpopulation of primed ESCs.
  • An Id-resistant Tcf15 mutant rapidly downregulates Nanog and promotes somatic lineage entry.
  • Tcf15 expression is dependent on FGF signaling, suggesting a role in differentiation priming.

Conclusions:

  • Id proteins may prime pluripotent cells for differentiation by regulating Tcf15 activity.
  • Tcf15 acts as a key mediator in the transition from pluripotency to somatic lineages.
  • FGF signaling primes cells for differentiation partly through Tcf15 regulation without compromising pluripotency.

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