Control of developmentally primed erythroid genes by combinatorial co-repressor actions

Nat Commun. 2015 Nov 23;6:8893. doi: 10.1038/ncomms9893.

Abstract

How transcription factors (TFs) cooperate within large protein complexes to allow rapid modulation of gene expression during development is still largely unknown. Here we show that the key haematopoietic LIM-domain-binding protein-1 (LDB1) TF complex contains several activator and repressor components that together maintain an erythroid-specific gene expression programme primed for rapid activation until differentiation is induced. A combination of proteomics, functional genomics and in vivo studies presented here identifies known and novel co-repressors, most notably the ETO2 and IRF2BP2 proteins, involved in maintaining this primed state. The ETO2-IRF2BP2 axis, interacting with the NCOR1/SMRT co-repressor complex, suppresses the expression of the vast majority of archetypical erythroid genes and pathways until its decommissioning at the onset of terminal erythroid differentiation. Our experiments demonstrate that multimeric regulatory complexes feature a dynamic interplay between activating and repressing components that determines lineage-specific gene expression and cellular differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Erythroid Cells / cytology
  • Erythroid Cells / metabolism*
  • Erythropoiesis
  • Gene Expression Regulation, Developmental*
  • Humans
  • LIM Domain Proteins / genetics
  • LIM Domain Proteins / metabolism
  • Mice
  • Molecular Sequence Data
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Nuclear Receptor Co-Repressor 1 / genetics
  • Nuclear Receptor Co-Repressor 1 / metabolism
  • Nuclear Receptor Co-Repressor 2 / genetics
  • Nuclear Receptor Co-Repressor 2 / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • CBFA2T3 protein, human
  • Carrier Proteins
  • DNA-Binding Proteins
  • IRF2BP2 protein, human
  • LDB1 protein, human
  • LIM Domain Proteins
  • NCOR1 protein, human
  • NCOR2 protein, human
  • Nuclear Proteins
  • Nuclear Receptor Co-Repressor 1
  • Nuclear Receptor Co-Repressor 2
  • Repressor Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins