Gene Regulation in Lymphocytes

Sen, Ranjan Sen

Abstract

During the current (2008) fiscal year we accomplished the following:? ? (1) Determined the contribution of Eμ to establishing tissue-specific chromatin state prior to initiation of recombination, its role in sterile transcription through a 400 kb region and its effect on DH to JH recombination. Eμ-deleted alleles exhibit a partially activated state characterized by normal depletion of H3K9me2 and gain of H34K4me2, but absence of H3 or H4 acetylation. These observations demonstrate an epigenetic hierarchy in tissue-specific locus activation.? ? (2) We used BAC engineering to move Eμ to different locations within the DH-Cμ domain of IgH. These BACs were used to generate transgenic mice. The first group of potential founders are being bred for further analysis.? ? (3) Completed analyzing the effects of the first step of recombination on chromatin structure in the IgH locus. We found localized alteration of activation modifications that provide a plausible mechanism for targeting VH gene recombination to the rearranged DJH junction.? ? (4) Completed analyzing DNA methylation in the IgH locus before, and after, initiation of recombination. We found that DJH junctions undergo localized CpG de-methylation in normal pro-B cells. This effect was absent in Eμ-deficient alleles indicating that de-methylation is directed by Eμ.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute on Aging (NIA)
• Type: Intramural Research (Z01)
• Project #: 1Z01AG000383-05
• Application #: 7732222
• Support Year: 5
• Fiscal Year: 2008
• Total Cost: $646,338

Institution

• Name: National Institute on Aging
• Country: United States

Publications

Rajagopal, Deepa; Maul, Robert W; Ghosh, Amalendu et al. (2009) Immunoglobulin switch mu sequence causes RNA polymerase II accumulation and reduces dA hypermutation. J Exp Med 206:1237-44

Liu, Yun; Subrahmanyam, Ramesh; Chakraborty, Tirtha et al. (2007) A plant homeodomain in RAG-2 that binds Hypermethylated lysine 4 of histone H3 is necessary for efficient antigen-receptor-gene rearrangement. Immunity 27:561-71

Mittal, Akanksha; Papa, Salvatore; Franzoso, Guido et al. (2006) NF-kappaB-dependent regulation of the timing of activation-induced cell death of T lymphocytes. J Immunol 176:2183-9

Sen, Ranjan (2006) Control of B lymphocyte apoptosis by the transcription factor NF-kappaB. Immunity 25:871-83

Sen, Ranjan; Oltz, Eugene (2006) Genetic and epigenetic regulation of IgH gene assembly. Curr Opin Immunol 18:237-42

Sen, Ranjan (2005) A move to exclude. Nat Immunol 6:128-30

Banerjee, Daliya; Liou, Hsiou-Chi; Sen, Ranjan (2005) c-Rel-dependent priming of naive T cells by inflammatory cytokines. Immunity 23:445-58

Chowdhury, Dipanjan; Sen, Ranjan (2004) Regulation of immunoglobulin heavy-chain gene rearrangements. Immunol Rev 200:182-96

Chowdhury, Dipanjan; Sen, Ranjan (2004) Mechanisms for feedback inhibition of the immunoglobulin heavy chain locus. Curr Opin Immunol 16:235-40

Sen, Ranjan (2004) NF-kappaB and the immunoglobulin kappa gene enhancer. J Exp Med 200:1099-102