Multivalent binding of the ETO corepressor to E proteins facilitates dual repression controls targeting chromatin and the basal transcription machinery

Mol Cell Biol. 2009 May;29(10):2644-57. doi: 10.1128/MCB.00073-09. Epub 2009 Mar 16.

Abstract

E proteins are a family of helix-loop-helix transcription factors that play important roles in cell differentiation and homeostasis. They contain at least two activation domains, AD1 and AD2. ETO family proteins and the leukemogenic AML1-ETO fusion protein are corepressors of E proteins. It is thought that ETO represses E-protein activity by interacting with AD1, which competes away p300/CBP histone acetyltransferases. Here we report that E proteins contain another conserved ETO-interacting region, termed DES, and that differential associations with AD1 and DES allow ETO to repress transcription through both chromatin-dependent and chromatin-independent mechanisms. At the chromatin level, AD1 and AD2 cooperatively recruit p300. ETO interacts with AD1 to abolish p300 recruitment and to allow HDAC-dependent silencing. At the post-chromatin-remodeling level, binding to DES enables ETO to directly inhibit activation of the basal transcription machinery. This novel repression mechanism is conserved in ETO family proteins and in the AML1-ETO fusion protein. In addition, the repression capacity exerted by each mechanism is differentially modulated by cross talk among various ETO domains and the AML1 domain of AML1-ETO. In particular, the oligomerization domain of ETO plays a major role in targeting ETO to the DES region and independently potentiates the TAFH domain-mediated AD1 interaction. The ability to exert repression at different levels not only may allow these corepressors to impose robust inhibition of signal-independent transcription but may also allow a rapid response to signals. In addition, our newly defined domain interactions and their interplays have important implications in effectively targeting both E-protein fusion proteins and AML1-ETO found in cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / chemistry
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Line
  • Chromatin / metabolism*
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / metabolism
  • Gene Expression Regulation*
  • Humans
  • Models, Molecular
  • Protein Binding
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RUNX1 Translocation Partner 1 Protein
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Chromatin
  • Core Binding Factor Alpha 2 Subunit
  • Proto-Oncogene Proteins
  • RUNX1 Translocation Partner 1 Protein
  • RUNX1 protein, human
  • RUNX1T1 protein, human
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Transcription Factors