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J. Biol. Chem., Vol. 279, Issue 29, 30850-30855, July 16, 2004

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A Signaling Role of Histone-binding Proteins and INHAT Subunits pp32 and Set/TAF-I in Integrating Chromatin Hypoacetylation and Transcriptional Repression^*

Sara N. Kutney, Rui Hong, Todd Macfarlan, and Debabrata Chakravarti¶

From the Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Various post-translational modifications of histones significantly influence gene transcription. Although un- or hypoacetylated histones are tightly linked to transcriptional repression, the mechanisms and identities of chromatin signal transducer proteins integrating histone hypoacetylation into repression in humans have remained largely unknown. Here we show that the mammalian histone-binding proteins and inhibitor of acetyltransferases (INHAT) complex subunits, Set/template-activating factor-I (TAF-I) and pp32, specifically bind to unacetylated, hypoacetylated, and repressively marked histones but not to hyperacetylated histones. Additionally, Set/TAF-I and pp32 associate with histone deacetylases in vitro and in vivo and repress transcription from a chromatin-integrated template in vivo. Finally, Set/TAF-I and pp32 associate with an endogenous estrogen receptor-regulated gene, EB1, in the hypoacetylated transcriptionally inactive state but not with the hyperacetylated transcriptionally active form. Together, these data define a novel in vivo mechanistic role for the mammalian Set/TAF-I and pp32 proteins as transducers of chromatin signaling by integrating chromatin hypoacetylation and transcriptional repression.

Received for publication, May 4, 2004

^* This work was supported by National Institutes of Health Grants DK65148 and DK57079 (to D. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by National Institutes of Health Training Grant 5-T32-GM-007229 from the predoctoral training program in cell and molecular biology.

Supported by National Institutes of Health Training Grant 5-T32-GM-00216–16 from the predoctoral training program in genetics.

^¶ To whom correspondence should be addressed. Tel.: 215-573-8470; Fax: 215-573-9004; E-mail: debu{at}pharm.med.upenn.edu.

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