Progress during FY18: 1) Demonstrated that E activates highly specific VH gene segments in the absence of a functional IGCR1. Choice of VHs is dictated by the next available CTCF binding site beyond IGCR1, to which E makes highly specific loops. As a consequence, recombination efficiency increases but diversity is greatly reduced. We propose that IGCR1 sequesters E in a manner that precludes E looping to very specific locations in the VH region. Thus, the immune system evolved to sacrifice efficiency to gain diversity. These observations were published in Molecular Cell (2018). 2) Demonstrated that VH genes can recombine by deletion as well as inversion to germline DH gene segments on IGCR1-mutated alleles. To the best of our knowledge this is the first demonstration of inversional recombination in the IgH locus. Preliminary results indicate that an inversional VDH junction cannot complete both recombination steps to generated VDJ recombined alleles. Manuscript in preparation. 3) Showed that distal VH gene segments recruit CTCF but not Rad21 in Thymocytes, thereby precluding the first step of locus compaction. These observations provide a plausible explanation for the lack of distal VH recombination even in Pax5-expressing thymocytes. A manuscript describing these is being revised for re-submission.
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