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T-Bet Dependent Removal of Sin3A-Histone Deacetylase Complexes at the Ifng Locus Drives Th1 Differentiation¹

Shaojing Chang^*, Patrick L. Collins^*, and Thomas M. Aune^2,*,

^* Division of Rheumatology, Department of Medicine and Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA

Forming and removing epigenetic histone marks at gene loci are central processes in differentiation. Here, we explored mechanisms establishing long-range H4 acetylation marks at the Ifng locus during Th1 lineage commitment. In Th0 cells, histone deacetylase (HDAC)-Sin3A complexes recruited to the Ifng locus actively prevented accumulation of H4 acetylation marks. Th1 differentiation caused loss of HDAC-Sin3A complexes by T-bet-dependent mechanisms and accumulation of H4 acetylation marks. HDAC-Sin3A complexes were absent from the locus in NOD Th0 cells, obviating the need for Th1 differentiation signals to establish histone marks and Th1 differentiation. Thus, Ifng transcription is actively prevented in Th0 cells via epigenetic mechanisms and epigenetic defects allow unregulated Ifng transcription that may contribute to autoimmunity.

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.

¹ This work was supported by Grants R01 AI 044924 and T32 HL069765 from the National Institutes of Health.

All authors contributed to discussions, experimental design, data analysis, execution of experiments, and preparation of the manuscript.

² Address correspondence and reprint requests to Thomas M. Aune, MCN T3219, Vanderbilt University Medical Center, 1161 21st Ave. S., Nashville, TN, 37232. E-mail address: tom.aune{at}vanderbilt.edu

³ Abbreviations used in this paper: HAT, histone acetyltransferases; HDAC, histone deacetylases; ChIP, chromatin immunoprecipitation; RV, retroviral; TSA, trichostatin A.