Faculty Lecture Series

When	Wednesday, February 10, 2010 5 PM - 6 PM
Where	Valerie Timken Amphitheater Green Hospital
Who		Ann Feeney, Ph.D. Professor, Department of Immunology and Microbial Science
Topic	"Genetic and Epigenetic Regulation of Antigen Receptor Gene Rearrangement"
	The antibody repertoire is enormous, and reflects the power of combinatorial and junctional diversity to generate a vast repertoire of antibodies through the intricate process of V(D)J recombination. In each precursor B lymphocyte, a different set of V, D, and J genes recombine at the level of genomic DNA to form exons encoding the light and heavy chains of the antibody molecule. Although there are many V, D, and J genes at each locus, the usage of these genes is highly unequal. One of our goals is to understand the basis of this non-random gene utilization. Another goal is to understand the precise regulation of the process of V(D)J recombination. There is much natural variation in the sequence of the recombinase binding site flanking each recombining gene segment, and this genetic variation contributes to unequal recombination frequencies. However, other factors also play a major role in recombination frequencies, as evidenced by the fact that some genes with identical recombinase binding sites rearrange at very different frequencies in vivo. Analysis of these gene segments by chromatin immunoprecipitation (ChIP) suggests that differences in chromatin structure of each gene is also a major factor in accessibility for rearrangement. In addition, transcription factors can direct accessibility for recombination, possibly by recruiting chromatin-modifying enzymes to the vicinity of the gene segment. Finally, in addition to these genetic and epigenetic levels of regulation, there is emerging evidence that the 3-dimensional structure of the antigen receptor loci changes uniquely and transiently during the process of V(D)J recombination by contracting and looping to bring the hundreds of V genes spread over the 2-3 megabase loci into close proximity to the DJ genes to which they need to recombine. Together, these genetic and epigenetic factors result in the finely orchestrated process of V(D)J rearrangement which creates a diverse antibody repertoire.
Selected Publications
	Feeney, A.J. Genetic and epigenetic control of V gene rearrangement frequency. Adv. Exp. Med. Biol. 650:73-81, 2009.
	Degner, S.C., Wong, T.P., Jankevicius, G., and Feeney, A.J. Cutting Edge: Developmental stage-specific recruitment of cohesin to CTCF sites throughout immunoglobulin loci during B lymphocyte development. J. Immunol. 182:44-48, 2009.
	Xu, C.-R. and Feeney, A.J. The epigenetic profile of immunoglobulin genes is dynamically regulated during B cell differentiation and is modulated by pre-BCR signaling. J. Immunol. 182:1362-1378, 2009.
	Xu, C.-R., Schaffer. L., Head, S.R. and Feeney, A.J. Reciprocal patterns of methylation of H3K36 and H3K27 on proximal vs. distal IgV_H genes are modulated by IL7 and Pax5. Proc Natl Acad Sci USA 105:8685-8690, 2008
	Espinoza, C.R. and Feeney, A.J. Chromatin accessibility and epigenetic modifications differ between frequently and infrequently rearranging VH genes. Mol. Immunol. 44: 2675-2685, 2007.