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Thanatos-Associated Protein 7 Associates with Template Activating Factor-Iß and Inhibits Histone Acetylation to Repress Transcription

Department of Pharmacology, University of Pennsylvania School of Medicine (T.M., J.B.P., D.C.), Philadelphia, Pennsylvania 19104; and Department of Infection Biology, Graduate School of Comprehensive Human Sciences and Institute of Basic Medical Sciences, University of Tsukuba (K.N.), Tsukuba 305-8575, Japan

Address all correspondence and requests for reprints to the present address: Dr. Debabrata Chakravarti, 4-119 Lurie Research Building, 303 East Superior Street, Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611. E-mail: debu{at}northwestern.edu.

The posttranslational modifications of histones on chromatin or a lack thereof is critical in transcriptional regulation. Emerging studies indicate a role for histone-binding proteins in transcriptional activation and repression. We have previously identified template-activating factor-Iß (TAF-Iß, also called PHAPII, SET, and I₂^pp2A) as a component of a cellular complex called inhibitor of acetyltransferases (INHAT) that masks histone acetylation in vitro and blocks histone acetyltransferase (HAT)-dependent transcription in living cells. TAF-Iß has also been shown to associate with transcription factors, including nuclear receptors, to regulate their activities. To identify novel interactors of TAF-Iß, we employed a yeast two-hybrid screen and identified a previously uncharacterized human protein called thanatos-associated protein-7 (THAP7), a member of a large family of THAP domain-containing putative DNA-binding proteins. In this study we demonstrate that THAP7 associates with TAF-Iß in vitro and map their association domains to a C-terminal predicted coiled-coil motif on THAP7 and the central region of TAF-Iß. Similarly, stably transfected THAP7 associates with endogenous TAF-Iß in intact cells. Like TAF-Iß, THAP7 associates with histone H3 and histone H4 and inhibits histone acetylation. The histone-interacting domain of THAP7 is sufficient for this activity in vitro. Promoter-targeted THAP7 can also recruit TAF-Iß and silencing mediator of retinoid and thyroid receptors/nuclear hormone receptor corepressor (NCoR) proteins to promoters, and knockdown of TAF-Iß by small interfering RNA relieves THAP7-mediated repression, indicating that, like nuclear hormone receptors, THAP7 may represent a novel class of transcription factor that uses TAF-Iß as a corepressor to maintain histones in a hypoacetylated, repressed state.

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