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* Department of Microbiology and Immunology, Vanderbilt University, Nashville, TN 37232;
Experimental Research Center for Infectious Diseases, Institute for Virus Research, Department of Molecular and Cellular Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan; and
Faculty of Biology, University of Freiburg and Max-Planck Institute of Immunobiology, Freiburg, Germany
Lymphocyte development is controlled by dynamic repression and activation of gene expression. These developmental programs include the ordered, tissue-specific assembly of Ag receptor genes by V(D)J recombination. Changes in gene expression and the targeting of V(D)J recombination are largely controlled by patterns of epigenetic modifications imprinted on histones and DNA, which alter chromatin accessibility to nuclear factors. An important component of this epigenetic code is methylation of histone H3 at lysine 9 (H3K9me), which is catalyzed by histone methyltransferases and generally leads to gene repression. However, the function and genetic targets of H3K9 methyltransferases during lymphocyte development remain unknown. To elucidate the in vivo function of H3K9me, we generated mice lacking G9a, a major H3K9 histone methyltransferase, in lymphocytes. Surprisingly, lymphocyte development is unperturbed in G9a-deficient mice despite a significant loss of H3K9me2 in precursor B cells. G9a deficiency is manifest as modest defects in the proliferative capacity of mature B cells and their differentiation into plasma cells following stimulation with LPS and IL-4. Precursor lymphocytes from the mutant mice retain tissue- and stage-specific control over V(D)J recombination. However, G9a deficiency results in reduced usage of Ig
L chains and a corresponding inhibition of Ig gene assembly in bone marrow precursors. These findings indicate that the H3K9me2 epigenetic mark affects a highly restricted set of processes during lymphocyte development and activation.
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1 This work was supported by National Institutes of Health Grants P01 HL68744 and CA100905 (to E.M.O.) and F32 AI066691-01A1 (to L.R.T.); Cancer Center Support Grant P30 CA68485, Vanderbilt-Ingram Cancer Center (to E.M.O.); a grant-in-aid from the Ministry of Education, Science, Technology, and Culture of Japan (to Y.S. and M.T.); the 21st Century Center of Excellence Program of the Ministry of Education, Culture, Sports, Science, Technology to the Graduate School of Biostudies (to H.M.); and Deutsche Forschungsgemeinschaft Grant SFB620, Teilprojekte B5 (to M.R.).
2 Address correspondence and reprint requests to Dr. Eugene M. Oltz, Department of Microbiology and Immunology, Vanderbilt University School of Medicine, 1161 21st Avenue South, Nashville, TN 37232. E-mail address: eugene.oltz{at}vanderbilt.edu
3 Abbreviations used in this paper: H3K9, histone 3 lysine 9; H3K9me1, me2, and me3, mono-, di-, and trimethylated forms of H3K9; HMT, histone methyltransferase; AID, activation-induced deaminase; CSR, class switch recombination; ChIP, chromatin immunoprecipitation; KLH, keyhole limpet hemocyanin; ES cells, embryonic stem cells; H3K9ac, acetylated H3K9.
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