Structural Features of Transcription Factors Associating with Nucleosome Binding

Meilin Fernandez Garcia, Cedric D. Moore, Katharine N. Schulz, Oscar Alberto, Greg Donague, Melissa M. Harrison, Heng Zhu, Kenneth S. Zaret

Research output: Contribution to journalArticle

Abstract

Fate-changing transcription factors (TFs) scan chromatin to initiate new genetic programs during cell differentiation and reprogramming. Yet the protein structure domains that allow TFs to target nucleosomal DNA remain unexplored. We screened diverse TFs for binding to nucleosomes containing motif-enriched sequences targeted by pioneer factors in vivo. FOXA1, OCT4, ASCL1/E12α, PU1, CEBPα, and ZELDA display a range of nucleosome binding affinities that correlate with their cell reprogramming potential. We further screened 593 full-length human TFs on protein microarrays against different nucleosome sequences, followed by confirmation in solution, to distinguish among factors that bound nucleosomes, such as the neuronal AP-2α/β/γ, versus factors that only bound free DNA. Structural comparisons of DNA binding domains revealed that efficient nucleosome binders use short anchoring α helices to bind DNA, whereas weak nucleosome binders use unstructured regions and/or β sheets. Thus, specific modes of DNA interaction allow nucleosome scanning that confers pioneer activity to transcription factors.

Original languageEnglish (US)
Pages (from-to)921-932.e6
JournalMolecular cell
Volume75
Issue number5
DOIs
StatePublished - Sep 5 2019

Keywords

  • Ascl1
  • FoxA
  • NHLH2
  • nucleosome binding
  • pioneer transcription factor
  • protein microarray
  • Pu.1
  • RBPJ
  • TFAP2A

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Fernandez Garcia, M., Moore, C. D., Schulz, K. N., Alberto, O., Donague, G., Harrison, M. M., Zhu, H., & Zaret, K. S. (2019). Structural Features of Transcription Factors Associating with Nucleosome Binding. Molecular cell, 75(5), 921-932.e6. https://doi.org/10.1016/j.molcel.2019.06.009