The Journal of Experimental Medicine
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Published online 2 April 2001.
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© The Rockefeller University Press, 0022-1007/2001/4/873/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 7, April 2, 2001 873-880

Brief Definitive Report

Histone Acetylation Determines the Developmentally Regulated Accessibility for T Cell Receptor {gamma} Gene Recombination

Yasutoshi Agataa, Tomoya Katakaia, Sang-Kyu Yeb, Manabu Sugaia, Hiroyuki Gondaa, Tasuku Honjob, Koichi Ikutab, and Akira Shimizua
a Center for Molecular Biology and Genetics, Kyoto University, Kyoto 606-8507, Japan
b Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan

Correspondence to: Yasutoshi Agata, Dept. of Biology, University of California, San Diego, La Jolla, CA 92093-0366. Tel:858-534-8797 Fax:858-534-7550 E-mail:yagata{at}biomail.ucsd.edu.

Variable/diversity/joining (V[D]J) recombination of the T cell receptor (TCR) and immunoglobulin (Ig) genes is regulated by chromatin accessibility of the target locus to the recombinase in a lineage- and stage-specific manner. Histone acetylation has recently been proposed as a molecular mechanism underlying the accessibility control. Here, we investigate the role for histone acetylation in the developmentally regulated rearrangements of the mouse TCR-{gamma} gene, wherein predominant rearrangement is switched from V{gamma}3 to V{gamma}2 gene during the fetal to adult thymocyte development. Our results indicate that histone acetylation correlates with accessibility, as histone acetylation at the fetal-type V{gamma}3 gene in accord with germline transcription is relatively high in fetal thymocytes, but specifically becomes low in adult thymocytes within the entirely hyperacetylated locus. Furthermore, inhibition of histone deacetylation during the development of adult bone marrow–derived thymocytes by a specific histone deacetylase inhibitor, trichostatin A, leads to elevated histone acetylation, germline transcription, cleavage, and rearrangement of the V{gamma}3 gene. These data demonstrate that histone acetyl- ation functionally determines the chromatin accessibility for V(D)J recombination in vivo and that an epigenetic modification of chromatin plays a direct role in executing a developmental switch in cell fate determination.

Key Words: V(D)J recombination, germline transcript, ligation-mediated PCR, chromatin immunoprecipitation, histone deacetylase


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