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OCT4 impedes cell fate redirection by the melanocyte lineage master regulator MITF in mouse ESCs

Danna Sheinboim1, Itay Maza2,3, Iris Dror4,5

  • 1Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.

Nature Communications
|October 19, 2017
PubMed

Insights

Mouse embryonic stem cells resist cell fate conversion due to Oct4. This pluripotency factor physically blocks MITF, preventing differentiation until Oct4 is removed, revealing key regulatory principles.

Area of Science:

  • Stem cell biology
  • Developmental biology
  • Epigenetics

Background:

  • Ectopic expression of lineage master regulators can induce cell fate transitions (transdifferentiation).
  • The capacity for cell fate transitions across different developmental stages remains largely unexamined.
  • Mouse embryonic stem cells (mESCs) are a key model for studying pluripotency and differentiation.

Purpose of the Study:

  • To investigate whether cell fate transitions can be induced across various developmental stages.
  • To determine the resistance of mESCs to cell fate conversion induced by the melanocyte master regulator MITF.
  • To elucidate the molecular mechanisms underlying Oct4's role in maintaining pluripotency and resisting differentiation.

Main Methods:

  • Generation of a transgenic system to study cell fate conversion.
  • Analysis of MITF-induced differentiation in mESCs at different developmental stages.
  • Investigation of Oct4's interaction with MITF using physical interference assays.
  • Chromatin architecture and ChIP-seq analysis to study Oct4 binding dynamics.

Main Results:

  • mESCs are resistant to cell fate conversion induced by MITF compared to other developmental stages.
  • The pluripotency factor Oct4 physically interferes with MITF's transcriptional activity in mESCs.
  • Release from Oct4-mediated pluripotency is necessary for ectopic differentiation induction in mESCs.
  • Oct4 induction in differentiated cells represses their lineage identity in vivo.
  • Oct4 competes with other lineage master regulators for binding to promoters and enhancers.

Conclusions:

  • Oct4 actively maintains pluripotency by counteracting differentiation signals like MITF through physical interference.
  • Cellular differentiation requires the release from Oct4-dependent pluripotency.
  • Oct4 plays a critical role in repressing lineage identity in differentiated cells, suggesting a broader role in cell fate regulation.
  • Findings reveal fundamental principles of pluripotency and transdifferentiation, with implications for regenerative medicine.

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