Anne Corcoran
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Chromatin re-organisation regulates V(D)J recombination
Understanding the role of chromatin and chromosome structure in controlling gene expression during the development of the immune system is the focus of our research.
B lymphocytes are cells of the immune system that produce antibodies (immunoglobulins), which recognise and inactivate foreign antigens like bacteria. To cope with the enormous numbers of foreign antigens encountered during our lifespan, these cells must produce millions of different antibodies. Recombination or ‘shuffling' of genes in the immunoglobulin heavy chain (IgH) locus is the first step in generating this huge repertoire. Special ‘marks’ on the chromatin are thought to underlie the complex choice of gene segments in the multigenic immunoglobulin gene families, that can be recombined during B cell development to produce a large diversity of functional antibody molecules. This group studies non-coding RNA transcription (ie generation of transcripts that do not produce protein) in specific parts of the immunoglobulin cluster, which may play a directive role in V(D)J recombination, or mark epigenetic control regions.
The IgH locus contains 200 variable (V) genes, 12 diversity (D) genes, and 4 joining (J) genes, which are cut and pasted together (recombination) in many different combinations; a D and a J gene are spliced together first, followed by a V gene (Figure 1). Only one of each gene type is used in an individual cell and the resulting DNA sequence encodes a unique IgH, which is expressed with an Ig light chain as a unique highly specific antibody in each cell (Figure 1).
Our aim is to understand the chromatin remodelling mechanisms that open up the IgH locus in B cells to enable V(D)J recombination. Chromatin (DNA wrapped around nucleosomes composed of histone proteins) is a highly compacted structure and inaccessible in non-B cells. It must be unfolded to give access to the enzymes RAG1 and RAG2 that catalyse the DNA breaks (cutting) of VDJ rearrangement. If the locus isn't opened up enough, too few antibodies are made, resulting in immunodeficiency. Conversely if it's opened up excessively, or not closed down after recombination, inappropriate DNA breaks may occur, which may be repaired incorrectly causing B cell lymphomas.
