Regulation of Accessibility of the Variable Gene Segments of the Mouse Immunoglobulin Kappa Light Chain Gene Locus

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Understanding the development of the expression of antibody heavy and light chain molecules is required to fully explain the adaptive immune response. This involves understanding the mechanisms underlying the selection of individual Vκ genes for V-J joining. It has been assumed that this selection involves alterations in the chromatin structure surrounding Vκ genes. Therefore, the focus of my work has centered on understanding the factors influencing the selection of a particular Vκ gene as well as the accompanying alterations in chromatin structure. I have assembled the complete nucleotide sequence of the 3.2 Mb Mus musculus Igκ gene locus and mapped all of the functional and pseudo-Vκ genes onto the sequence. I have also determined the patterns of potential transcription factor binding sites surrounding these Vκ genes. These analyses revealed statistically significant patterns of transcription factor motifs that are clustered either upstream of the transcription start site, in the intronic region, or downstream of the recombination signal sequence (RSS). The conservation of these sites has been tied to the presence of DNase I hypersensitive sites at the pre-B cell stage of development. These hypersensitive sites appear just prior to the V-J joining step and disappear after the Igκ locus has completed the rearrangement process. These sites are present at or near the promoter of the particular Vκ gene and are sometimes present near the RSS as well. I also looked for the presence of transcripts from the promoters of the Vκ genes that had HSP and HSRSS. I found that the presence of transcripts and the presence of HS was uncoupled. There were instances where both HS and transcripts were present, neither was present, or only one phenomenon was observed. This led me to conclude that these events were separable. The presence of HSRSS as well as the corresponding binding sites for transcription factors in the downstream region, suggests a model for generating accessibility of Igκ V genes for V-J joining.

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