简介

The immune system is our spacesuit for life in an environment containing enormous numbers of infectious agents. An essential part of the immune system is the B cell, which is the only cell type that produces antibodies. Antibody (Ig) genes are constructed via a series of DNA rearrangements. Occasionally, mistakes occur during antibody construction, which activate oncogenes and lead to cancers. My long term goal is to understand the mechanisms that initiate and control antibody gene rearrangements within the 3 megabase heavy chain gene (IgH) locus. Our experiments focus on a complex 3' IgH regulatory "ignition" region that lies immediately downstream of the antibody heavy chain gene cluster in mouse and humans. The ~50 kb 3' IgH regulatory region (3’ RR), containing multiple regulatory elements, and a 1 kb intronic enhancer, are the only two currently known regulatory regions for the Igh locus. We have recently identified an extension of the 3’ RR (hs5, 6, 7), which like the other 3' enhancers, has binding sites for Pax5, a transcription factor essential for B cell development. In addition, the 3' RR extension contains insulator activity, i.e. prevention of communication between an enhancer and its target promoter. This is associated with binding sites for CTCF, a protein identified in all mammalian insulators. Chromatin analysis shows that the 3' RR extension is likely to be active throughout B cell development while other 3' RR segments become progressively and stage-specific active.