A functional immune system is central to human health and, at the same time, alterations of normal lymphoid developmental programs can lead to immune deficiencies, autoimmune diseases and a variety of lymphomas. Germinal centers (GCs) are microanatomical structures formed in secondary lymphoid organs during antigen- stimulated immune responses. GCs are the sites of B cell maturation through clonal expansion, somatic hypermutation, and affinity-mediated selection -- and therefore play a critical role in differentiation of antibody secreting cells and memory B cells. OCA-B is a unique transcriptional coactivator that is highly expressed in GC B cells and GC-derived lymphomas such as diffuse large B cell lymphoma and Burkitt?s lymphoma. In vivo studies have demonstrated that OCA-B is essential for both antigen-dependent B cell differentiation (including GC formation) and normal expression of secondary immunoglobulin genes. However, little is known about the exact role of OCA-B in normal GC formation and GC-derived lymphoma progression. In addition, the mechanism by which OCA-B regulates its target genes is also unclear. In addressing these issues, our preliminary studies have demonstrated (i) a functional occupancy of OCA-B on distal enhancers, in particular the large locus control region (LCR) of the BCL6 gene that encodes a master regulator of GC formation; (ii) direct interactions of OCA- B with the MED1 subunit of the Mediator coactivator complex and with a GC-specific transcription factor (MEF2B) important for BCL6 expression and (iii) a B cell-intrinsic Oca-B dependency for GC B cell differentiation in vivo. Based on our previous OCA-B studies and recent preliminary data, we hypothesize that a predominant role of OCA-B in GC formation involves activation of BCL6 through its distal enhancer region by recruiting and concentrating transcription factors and cofactors, including chromatin/epigenetic factors, that facilitate enhancer- promoter interactions. We also hypothesis that OCA-B plays a critical role in GC-derived lymphomagenesis. To address these issues, we will investigate (i) the function and mechanism of action of OCA-B, through interactions with MED1/Mediator and MEF2B, on the BCL6 LCR/super-enhancer in both ex vivo GC B and lymphoma cells, (ii) the mechanism of action of OCA-B-dependent transcriptional coactivation through rigorous biochemical in vitro transcription assays; (iii) the mechanism of action of OCA-B in GC B cell differentiation in vivo, including identification of key target genes and regulatory networks; (iv) the role of OCA-B in B cell lymphoma progression in vivo. We will use complementary biochemical, genomic, bioinformatic, genetic, gene-editing, cell-based and in vivo (mouse model) approaches. Completion of these aims will advance our understanding of the molecular mechanism of action of OCA-B in GC-specific transcriptional regulation, GC B cell differentiation, and GC- derived B cell lymphomagenesis. Notably, it also will provide clues to new therapeutic strategies for treating B cell lymphomas.

Public Health Relevance

This study will identify target genes and mechanisms of action of a B cell-specific transcriptional co-activator (OCA-B) that has been demonstrated to be essential for germinal center (GC) formation and implicated in GC- derived lymphomas. This study will advance our understanding of humoral immune responses and provide insights into the development of new therapeutic strategies for immune deficiencies, autoimmune diseases and lymphomas.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Molecular Genetics A Study Section (MGA)
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Ferguson, Stacy E
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Rockefeller University
New York
United States
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