Co-ordination of recombination and allelic exclusion at IgH and Igk loci

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DESCRIPTION (provided by applicant): The molecular details of how faithful DNA rearrangements are maintained in the context of the complex chromatin environment of the developing B lymphocyte is the focus of ongoing research in my lab. We have new data indicating that the IgH locus is regulated by the Ig??locus and have identified the involvement of two Ig??regulatory elements, the 3'E??enhancer and Sis (silencer in the intervening sequence. Regulation is achieved through transient association of the two loci at the pro- to pre-B cell transition when the recombinase enzymes are targeted away from the IgH locus to the Ig? locus. We aim to elucidate the functional significance of association between the two loci and to understand in molecular detail how association is achieved. It is our hypothesis that association of the IgH and Ig??loci plays a central role in enforcing allelic exclusion of the IgH locus, which is critical for maintaining the integrity of the recombination process and ensuring genome stability. Because de-regulation of recombination and allelic exclusion can result in immune deficiency, autoimmunity and translocations involving Ig loci, it is essential to understand the underlying mechanisms. In addition these studies have important implications for gene regulation as a whole. Public Health Relevance Statement: The ordered rearrangement of immunoglobulin (Ig) genes is a highly regulated process essential for adaptive immunity, orchestrating the expression of B and T lymphocyte receptors through allelic exclusion that ensures clonality, all the while protecting the genome from these inherently unstable recombination events. The molecular details of how faithful DNA rearrangements are maintained in the context of the complex chromatin environment of the developing B lymphocyte is the focus of ongoing research in my lab. Our recent studies indicate that the pericentric Ig? allele directs the unrearranged IgH allele towards a shared pericentromeric cluster. Association of the two loci in this repressive environment subsequently induces IgH locus decontraction on the non-functional allele. This identifies a novel mechanism for co-ordinating changes in accessibility and expression. The hypothesis to be tested is that association of IgH and Ig? loci plays a central role in enforcing allelic exclusion of the IgH locus, which is critical for maintaining the integrity of the recombination process and ensuring genome stability. The aims in this grant are designed to understand in molecular detail the mechanisms by which association of Ig loci contributes to allelic exclusion and genome stability. Understanding how changes at the two loci are co-ordinated and identifying the pathways involved is of fundamental importance in the field because de-regulation of recombination and allelic exclusion can result in immune deficiency, autoimmunity and translocations that involve Ig loci. These studies provide new detail to the basic mechanisms linking immunoglobulin gene transcription and rearrangement and paint a picture of a highly dynamic and ordered nuclear architecture that will have important implications for gene regulation in general.