One of the first steps in successful B cell development is establishing an accessible, or open, immunoglobulin mu (IgM) chromatin structure. Increased accessibility is critical for converting the quiescent IgM locus of the hematopoietic precursor into a biologically functional, or activated, locus in the first committed member of the B lineage. However, the mechanisms regulating IgM accessibility are unknown. The proposed work will focus on determining how an inaccessible, or closed, mu chromatin structure becomes accessible during B cell development then remains accessible in the mature B cell. This work will answer the question: how is the mu enhancer activated in the context of chromatin? Completing the proposed work represents a first step towards the long-term goal of characterizing mechanisms driving tissue-specific regulation of IgM transcription. Work from multiple investigators spanning 20 years suggests that alterations in chromatin packaging regulate mu enhancer activation during B cell development. Increased mu enhancer accessibility, a prelude to full activation, correlates with transcription factor binding and modification of histone proteins packaging the mu enhancer. However, a direct """"""""cause and effect"""""""" relationship showing transcription factors directing changes in chromatin structure has not been established. Overall, we will test the hypothesis that the mu enhancer, and hence B cell development is regulated by transcription factor-directed histone modifications through three approaches: 1. We will define the combination of proteins required for establishing maximal accessibility from a naturally chromatinized mu locus by ectopically expressing transcription factors in cells; 2. We will destroy DNA binding activity of the accessibility factors then measure stability of the open mu chromatin structure; 3. We will test how transcription factors that induce mu accessibility affect acetylation and methylation of the histones packaging the mu enhancer by chromatin immunoprecipitation. Understanding the details of mu locus accessibility during B cell development will provide logical targets for pharmaceutically controlling B cell generation in disease states by either blocking or enhancing this developmentally critical process. In addition understanding the rules for tissue-specific gene expression will allow exquisitely regulated delivery of treatments for a variety of single tissue syndromes from cancer to diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054611-05
Application #
7121622
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Nasseri, M Faraz
Project Start
2003-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
5
Fiscal Year
2006
Total Cost
$236,557
Indirect Cost
Name
Boston University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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Jagannathan-Bogdan, Madhumita; McDonnell, Marie E; Shin, Hyunjin et al. (2011) Elevated proinflammatory cytokine production by a skewed T cell compartment requires monocytes and promotes inflammation in type 2 diabetes. J Immunol 186:1162-72
Jagannathan, M; McDonnell, M; Liang, Y et al. (2010) Toll-like receptors regulate B cell cytokine production in patients with diabetes. Diabetologia 53:1461-71
Nikolajczyk, Barbara S (2010) B cells as under-appreciated mediators of non-auto-immune inflammatory disease. Cytokine 50:234-42
Denis, Gerald V; Nikolajczyk, Barbara S; Schnitzler, Gavin R (2010) An emerging role for bromodomain-containing proteins in chromatin regulation and transcriptional control of adipogenesis. FEBS Lett 584:3260-8
Ganley-Leal, Lisa M; Liang, YanMei; Jagannathan-Bogdan, Madhumita et al. (2010) Differential regulation of TLR4 expression in human B cells and monocytes. Mol Immunol 48:82-8
Shin, Hyunjin; Zhang, Yue; Jagannathan, Madhumita et al. (2009) B cells from periodontal disease patients express surface Toll-like receptor 4. J Leukoc Biol 85:648-55
Jagannathan, Madhumita; Hasturk, Hatice; Liang, Yanmei et al. (2009) TLR cross-talk specifically regulates cytokine production by B cells from chronic inflammatory disease patients. J Immunol 183:7461-70
Zhang, Yue; Saccani, Simona; Shin, Hyunjin et al. (2008) Dynamic protein associations define two phases of IL-1beta transcriptional activation. J Immunol 181:503-12
Nikolajczyk, Barbara S; Sardi, Sylvia H; Tumang, Joseph R et al. (2007) Immunoglobulin kappa enhancers are differentially regulated at the level of chromatin structure. Mol Immunol 44:3407-15

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