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J. Biol. Chem., Vol. 279, Issue 39, 40640-40646, September 24, 2004

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Discrete Roles for Histone Acetylation in Human T Helper 1 Cell-specific Gene Expression^*

Akio Morinobu, Yuka Kanno, and John J. O'Shea¶

From the Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, NIAMS, National Institutes of Health, Bethesda, Maryland 20892

To better understand the control of T helper (T_H) 1-expressed genes, we compared and contrasted acetylation and expression for three key genes, IFNG, TBET, and IL18RAP and found them to be distinctly regulated. The TBET and the IFNG genes, but not the IL18RAP gene, showed preferential acetylation of histones H3 and H4 during T_H1 differentiation. Analysis of acetylation of specific histone residues revealed that H3(Lys-9), H4(Lys-8), and H4(Lys-12) were preferentially modified in T_H1 cells, suggesting a possible contribution of acetylation of these residues for induction of these genes. On the other hand, the acetylation of IL18RAP gene occurred both in T_H1 and T_H2 cells the similar kinetics and on the same with residues, demonstrating that selective histone acetylation was not universally the case for all T_H1-expressed genes. Histone H3 acetylation of IFNG and TBET genes occurred with different kinetics, however, and was distinctively regulated by cytokines. Interleukin (IL)-12 and IL-18 enhanced the histone acetylation of the IFNG gene. By contrast, histone acetylation of the TBET gene was markedly suppressed by IL-4, whereas IL-12 and IL-18 had only modest effects suggesting that histone acetylation during T_H1 differentiation is a process that is regulated by various factors at multiple levels. By treating Th2 cells with a histone deacetylase inhibitor, we restored histone acetylation of the IFNG and TBET genes, but it did not fully restore their expression in T_H2 cells, again suggesting that histone acetylation explains one but not all the aspects of T_H1-specific gene expression.

Received for publication, July 7, 2004

^* 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.

Both authors contributed equally to this work.

Current address: Dept. of Clinical Pathology and Immunology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail: morinobu{at}med.kobe-u.ac.jp.

^¶ To whom correspondence should be addressed: Bldg. 10, Rm. 9N252, 10 Center Dr., MSC-1820, NIH, Bethesda, MD 20892-1820. Tel.: 301-496-2541; Fax: 301-402-0012; E-mail: osheajo{at}mail.nih.gov.

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