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Targeted inhibition of V(D)J recombination by a histone methyltransferase

Nature Immunology volume 5, pages 309–316 (2004)Cite this article

Abstract

The tissue- and stage-specific assembly of antigen receptor genes by V(D)J recombination is regulated by changes in the chromatin accessibility of target gene segments. This dynamic remodeling process is coordinated by cis-acting promoters and enhancers, which function as accessibility control elements. The basic epigenetic mechanisms that activate or repress chromatin accessibility to V(D)J recombinase remain unclear. We now demonstrate that a histone methyltransferase overrides accessibility control element function and cripples V(D)J recombination of chromosomal gene segments. The recruited histone methyltransferase induces extensive revisions in the local chromatin environment, including altered histone modifications and de novo methylation of DNA. These findings indicate a key function for histone methyltransferases in the tissue- and stage-specific suppression of antigen receptor gene assembly during lymphocyte development.

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Figure 1: Functional targeting of G9a methyltransferase to chromosomal gene segments.
Figure 2: Recruitment of G9a alters the local pattern of histone modifications.
Figure 3: G9a inhibits germline transcription and V(D)J recombination.
Figure 4: Recruitment of G9a induces DNA methylation at chromosomal gene segments.
Figure 5: G9a inhibits V(D)J recombination independent of RSS methylation.

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Acknowledgements

We thank M. Sikes (North Carolina State University), K. Oestreich and H. Vekony (Vanderbilt University) for pilot studies during the initial stages of this project. We also thank D. Ballard (Vanderbilt University) for comments. Supported by the National Institutes of Health (P01 HL68744 and AI49934, E.M.O.; AI49934 and GM41052, M.S.K.), the Ministry of Education, Science, Sports, Culture, and Technology of Japan (Y.S.) and a Cancer Center Support Grant (P30 CA68485, Vanderbilt-Ingram Cancer Center).

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Vanderbilt University, Nashville, 37232, Tennessee, USA

    Oleg Osipovich, Robin Milley & Eugene M Oltz

  2. Department of Immunology, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Amber Meade & Michael S Krangel

  3. Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan

    Makoto Tachibana & Yoichi Shinkai

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Correspondence to Eugene M Oltz.

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Osipovich, O., Milley, R., Meade, A. et al. Targeted inhibition of V(D)J recombination by a histone methyltransferase. Nat Immunol 5, 309–316 (2004). https://doi.org/10.1038/ni1042

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