B cell development leads to the generation of a diverse repertoire of B lymphocytes, which provide antibody mediated immunity against pathogens. Central to understanding B cell development and related immune disorders is the regulation of lineage and stage specific V(D)J recombination within the immunoglobulin heavy and light chain gene loci. While many cis regulatory elements have been defined within these B cell receptor gene loci, much less is known about how these regulatory elements are recognized by and/or become accessible to transcription factors and recombination machineries. The bHLH transcription factors encoded by the E2A gene have been shown to play critical roles throughout B cell development. Among its broad functions in B cell development, compelling evidence is now available to suggest that E2A is both necessary and sufficient in activating IgK locus during pre-B cell development. How E2A accomplishes this lineage specific and stage specific regulatory event is not known. Research conducted during the previous project cycle provided us some critical information and valuable genetic tools to address this important question. In the current proposal, we propose three specific aims:
In Aim 1 we will investigate the mechanism by which E2A activates germline transcription and rearrangement at the IgK locus.
Aim 2 will investigate the role of E2A in IgK allelic exclusion, which is an important control mechanism responsible to prevent production of B cells with dual antigen specificity. Finally, we will expand our understanding of E2A mediated gene regulation by searching and investigating novel E2A interacting molecules in pre-B cells. The overall goal of this proposal is to use E2A mediated IgK activation system to reveal fundamental molecular mechanisms underlying B cell development. In addition to the knowledge gained in basic sciences, information generated from this study should help understand how genetic defects in B cell development may lead to immune disorders such as leukemia and autoimmune diseases.
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