Transcriptional Control of AICDA Expression

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DESCRIPTION (provided by applicant): Immunoglobulin somatic hypermutation and class switch recombination increase the specificity and expand the functionality of the antibody repertoire in response to antigenic challenge to provide better protection against infections. Both processes involve highly ordered, temporal destabilization of the genome in mature B lymphocytes. Regulation of this genomic destabilization appears to be crucial in controlling lymphoid tumorgenesis. One important regulatory mechanism is the transcriptional control of expression of the activation-induced cytidine deaminase (AICDA) gene. AICDA provides a central catalytic activity to both hypermutation and class switch recombination, is the only known lymphoid-specific component of both processes and its transcription is predominantly restricted to germinal center B-lymphocytes. Characterization of the transcriptional control of AICDA gene expression is essential to understand the physiological regulation of hypermutation and class switch recombination and could illuminate potential pathological aberrations that lead to uncontrolled genomic instability and tumorgenesis. We have characterized the transcription of the AICDA gene in murine B-cell lines, determined the transcription start site in established cell lines and primary, splenic B-cells and identified a putative promoter of the AICDA gene which is evolutionarily conserved. In this application, we propose to perform experiments to: i) identify additional regulatory regions within the AICDA locus, ii) establish transgenic models to test the function of candidate regulatory elements, and iii) perform biochemical characterization of DNA-protein interactions of the regulatory elements in vivo to identify candidate transcription factors that may be critical in the control of AICDA expression. The results of this pilot proposal will allow us to begin studies on the cellular signal transduction pathways and transcriptional regulatory factors that control somatic hypermutation and class switch recombination of immunoglobulin genes.