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Distinct associations of pioneer factor Ascl1-E12a with nucleosomes drive changes in cell fate

Bing-Rui Zhou1, Edgar Luzete-Monteiro2, Jingchao Zhang3

  • 1Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Molecular Cell
|June 12, 2026
PubMed

Insights

Pioneer transcription factors like Ascl1-E12a initiate cell fate changes by directly interacting with nucleosomal DNA. Specific binding mechanisms are crucial for overcoming chromatin barriers and enabling cellular reprogramming.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Developmental Biology

Background:

  • Pioneer transcription factors are key regulators of cell fate determination.
  • Understanding their interaction with chromatin is essential for deciphering early developmental events.
  • The Ascl1-E12a heterodimer plays a critical role in neural cell fate induction.

Purpose of the Study:

  • To investigate the molecular mechanisms by which the Ascl1-E12a pioneer factor targets and perturbs nucleosomal DNA.
  • To elucidate how these interactions facilitate chromatin accessibility and initiate cell fate changes.
  • To determine the role of distinct nucleosome association modes in pioneer factor function.

Main Methods:

  • Integrated structural, biochemical, and genomic approaches were employed.
  • In vitro nucleosome binding and DNA manipulation assays were performed.
  • In vivo chromatin targeting and cellular reprogramming efficiencies were assessed using Ascl1 mutants.

Main Results:

  • The Ascl1-E12a heterodimer binds nucleosomal DNA in a stepwise manner, involving DNA unwrapping and shifting.
  • Two distinct nucleosome association modes enhance binding affinity and modulate DNA dynamics.
  • Mutations affecting nucleosome association impair chromatin opening and cellular reprogramming in vivo.

Conclusions:

  • Distinct associations with nucleosomes are essential for pioneer factor Ascl1 function.
  • These interactions enable Ascl1 to overcome chromatin barriers and reprogram cell fate.
  • The findings provide critical insights into the earliest events of chromatin accessibility and cell fate determination.
Keywords:
cell fatechromatinchromatin openingcross-linkingcryo-EMneuralneuronnucleosomenucleosome arrayspioneer factorreprogramming

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