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Molecular and Cellular Biology, May 2009, p. 2644-2657, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.00073-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Multivalent Binding of the ETO Corepressor to E Proteins Facilitates Dual Repression Controls Targeting Chromatin and the Basal Transcription Machinery{triangledown} ,{ddagger}

Chun Guo, Qiande Hu, Chunxia Yan,{dagger} and Jinsong Zhang*

Department of Cancer and Cell Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, Ohio

Received 16 January 2009/ Accepted 4 March 2009

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.

* Corresponding author. Mailing address: Department of Cancer and Cell Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, 3125 Eden Avenue, Cincinnati, OH 45267-0521. Phone: (513) 558-1157. Fax: (513) 558-4454. E-mail: Jinsong.Zhang{at}uc.edu

{triangledown} Published ahead of print on 16 March 2009.

{ddagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{dagger} Present address: Forensic Department and the Key Laboratory of Health Ministry for Forensic Sciences, Xi'an Jiaotong University School of Medicine, 76 West Yanta Road, Xi'an, Shaanxi, People's Republic of China.

Molecular and Cellular Biology, May 2009, p. 2644-2657, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.00073-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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