Pioneer transcription factors target partial DNA motifs on nucleosomes to initiate reprogramming

Cell. 2015 Apr 23;161(3):555-568. doi: 10.1016/j.cell.2015.03.017. Epub 2015 Apr 16.

Abstract

Pioneer transcription factors (TFs) access silent chromatin and initiate cell-fate changes, using diverse types of DNA binding domains (DBDs). FoxA, the paradigm pioneer TF, has a winged helix DBD that resembles linker histone and thereby binds its target sites on nucleosomes and in compacted chromatin. Herein, we compare the nucleosome and chromatin targeting activities of Oct4 (POU DBD), Sox2 (HMG box DBD), Klf4 (zinc finger DBD), and c-Myc (bHLH DBD), which together reprogram somatic cells to pluripotency. Purified Oct4, Sox2, and Klf4 proteins can bind nucleosomes in vitro, and in vivo they preferentially target silent sites enriched for nucleosomes. Pioneer activity relates simply to the ability of a given DBD to target partial motifs displayed on the nucleosome surface. Such partial motif recognition can occur by coordinate binding between factors. Our findings provide insight into how pioneer factors can target naive chromatin sites.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Cell Dedifferentiation
  • Cellular Reprogramming*
  • DNA / metabolism
  • Fibroblasts / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / metabolism
  • Models, Molecular
  • Nucleosomes / metabolism*
  • Nucleotide Motifs
  • Octamer Transcription Factor-3 / metabolism
  • Protein Structure, Tertiary
  • Sequence Alignment
  • Transcription Factors / chemistry
  • Transcription Factors / classification
  • Transcription Factors / metabolism*

Substances

  • Nucleosomes
  • Octamer Transcription Factor-3
  • Transcription Factors
  • DNA