Multivalent binding of the ETO corepressor to E proteins facilitates dual repression controls targeting chromatin and the basal transcription machinery.
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.
Mesh Terms:
Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Line, Chromatin, Core Binding Factor Alpha 2 Subunit, Gene Expression Regulation, Humans, Models, Molecular, Protein Binding, Proto-Oncogene Proteins, RUNX1 Translocation Partner 1 Protein, Recombinant Fusion Proteins, Repressor Proteins, Transcription Factors, Transcription, Genetic
Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Line, Chromatin, Core Binding Factor Alpha 2 Subunit, Gene Expression Regulation, Humans, Models, Molecular, Protein Binding, Proto-Oncogene Proteins, RUNX1 Translocation Partner 1 Protein, Recombinant Fusion Proteins, Repressor Proteins, Transcription Factors, Transcription, Genetic
Mol Cell Biol
Date: May. 01, 2009
PubMed ID: 19289505
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