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Scripps Research Joint Appointments

Faculty, Kellogg School of Science and Technology

Research Focus

 

Epigenetic, genetic and transcriptional control of B cell differentiation and B cell repertoire formation

A main focus of our lab is the molecular analysis of the epigenetic, genetic and transcriptional mechanisms which regulate accessibility of the V, D, and J immunoglobulin (Ig) gene segments for V(D)J recombination, and elucidation of the factors which influence the composition of the initial antibody repertoire. Although there are many V, D, and J genes at each locus, we have previously shown that different gene segments rearrange with quite different relative frequencies in pro-B cells in vivo. One of our goals is to understand the basis of this non-random gene utilization. New technologies such as ChIP-seq and deep sequencing of the antibody repertoire are greatly aiding our research. We are analyzing the chromatin modifications that accompany B cell differentiation in vivo in an effort to understand the mechanism of lineage-specific and stage-specific control of accessibility of Ig genes, as well as to understand the control of rearrangement on the level of individual genes.  3D-FISH  and chromosome conformation capture are being used to study the changes in the 3-dimensional structure of the locus by transcription factors and by the CTCF/cohesin complex. A related issue is to determine what controls the changes in the epigenetic profile and in the 3-dimensional structure of the receptor loci at the developmental stage at which they undergo rearrangement. A likely group of candidates regulating the changes at the Igh locus are transcription factors that are critically involved in B cell differentiation and/or in compaction of the Igh locus. Current studies are aimed at identifying where the transcription factors bind, and elucidating the mechanism by which transcription factors control V(D)J rearrangement and B cell differentiation. We are also interested in the role of antibody repertoire specificities in controlling cell fate decisions, such as marginal zone B cells vs. follicular B cells, and the role of epigenetic regulation in later stages of B cell development. Finally, we are studying the epigenetic regulation of later steps in B cell differentiation, and how they are misregulated in B cell lymphoma.

Selected References

Degner SC, Verma-Gaur J, Wong TP, Bossen C, Iverson GM, Torkamani A, Vettermann C, Lin YC, Ju Z, Schulz D, Murre CS, Birshtein BK, Schork NJ, Schlissel MS, Riblet R, Murre C, Feeney AJ. CCCTC-binding factor (CTCF) and cohesin influence the genomic architecture of the Igh locus and antisense transcription in pro-B cells. Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9566-71. Epub 2011 May 23.

Feeney AJ. Epigenetic regulation of antigen receptor gene rearrangement. Curr Opin Immunol. 2011 Apr;23(2):171-7. Epub 2011 Jan 7. Review.

Degner-Leisso, S.C., and Feeney, A. J.  Epigenetic and 3-dimensional regulation of V(D)J rearrangement in immunoglobulin genes.  Seminars in Immunol. 22:346-52, 2010.

Lukin, K., Fields, S., Lopez, D., Cherrier, M., Ternyak, K., Ramirez, J., Feeney, A.J., Hagman, J. Compound haploinsufficiencies of Ebf1 and Runx1 genes impede B cell lineage progression. Proc Natl Acad Sci USA, 107:7869-7874, 2010.

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. Chosen as a featured article in "In This Issue".

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. Evaluated by the Faculty of 1000 Biology.

Carey, J.B., Moffatt-Blue, C.S., Watson, L.C., Gavin, A.L. and Feeney, A.J. Repertoire-based selection into the marginal zone compartment during B cell development. J. Exp. Med. 205:2043-2045, 2008. Evaluated by the Faculty of 1000 Biology.

Xu, C.R., Schaffer. L., Head, S.R. and Feeney, A.J.  Reciprocal patterns of methylation of H3K36 and H3K27 on proximal vs. distal IgVH genes are modulated by IL7 and Pax5. Proc Natl Acad Sci USA 105:8685-8690, 2008.

Lamoureux, J.L., Watson, L.C., Cherrier, M., Skog, P., Nemazee, D. and Feeney, A.J. Reduced receptor editing in lupus-prone MRL/lpr mice. J. Exp. Med. 204:2853-2864, 2007.