ResearchThe 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.
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.
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, a defect in the ability to fight infections.
Ageing can also result in a reduced antibody repertoire, which contributes to impaired response to infections in elderly people. 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.