Cofactor-mediated restriction of GATA-1 chromatin occupancy coordinates lineage-specific gene expression

Mol Cell. 2012 Aug 24;47(4):608-21. doi: 10.1016/j.molcel.2012.05.051. Epub 2012 Jul 5.


GATA-1 and its cofactor FOG-1 are required for the differentiation of erythrocytes and megakaryocytes. In contrast, mast cell development requires GATA-1 and the absence of FOG-1. Through genome-wide comparison of the chromatin occupancy of GATA-1 and a naturally occurring mutant that cannot bind FOG-1 (GATA-1(V205G)), we reveal that FOG-1 intricately regulates the chromatin occupancy of GATA-1. We identified GATA1-selective and GATA-1(V205G)-selective binding sites and show that GATA-1, in the absence of FOG-1, occupies GATA-1(V205G)-selective sites, but not GATA1-selective sites. By integrating ChIP-seq and gene expression data, we discovered that GATA-1(V205G) binds and activates mast cell-specific genes via GATA-1(V205G)-selective sites. We further show that exogenous expression of FOG-1 in mast cells leads to displacement of GATA-1 from mast cell-specific genes and causes their downregulation. Together these findings establish a mechanism of gene regulation whereby a non-DNA binding cofactor directly modulates the occupancy of a transcription factor to control lineage specification.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Binding Sites
  • Cells, Cultured
  • Chromatin / genetics*
  • Chromatin / metabolism*
  • Down-Regulation
  • GATA1 Transcription Factor / genetics*
  • GATA1 Transcription Factor / metabolism*
  • Gene Expression Regulation* / genetics
  • Mast Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • Proto-Oncogene Protein c-fli-1 / genetics
  • Proto-Oncogene Protein c-fli-1 / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism


  • Chromatin
  • Fli1 protein, mouse
  • GATA1 Transcription Factor
  • Gata1 protein, mouse
  • Nuclear Proteins
  • Proto-Oncogene Protein c-fli-1
  • Transcription Factors
  • Zfpm1 protein, mouse
  • Stub1 protein, mouse
  • Ubiquitin-Protein Ligases

Associated data

  • GEO/GSE31331
  • GEO/GSE35708