BBS Faculty Member - Marjorie Oettinger

Marjorie Oettinger

Department of Genetics

Massachusetts General Hospital
Simches Research Building CPZN-7240
185 Cambridge St.
Boston, MA 02114
Tel: 617-726-5967
Fax: 617-726-5949
Email: oettinger@molbio.mgh.harvard.edu
Lab Members: 5 postdoctoral fellows



The vertebrate immune system is capable of specifically recognizing and responding to an enormous number of antigens. The interaction with antigen is mediated by the immunoglobulin (Ig) and T cell receptor (TCR) molecules expressed by B and T lymphocytes respectively. Ig and TCR genes are encoded by multiple segments of DNA that are not contiguous in the germ line but are joined together in developing lymphocytes by a process known as V(D)J recombination. The various projects in my laboratory are connected by one central theme: we seek to understand all facets of V(D)J rearrangement, namely the enzymatic and regulatory machinery involved, the mechanism of the reaction, and the role of chromatin structure in the regulation of recombination events during lymphoid development. In addition, we are interested in how errors in this process lead to various human diseases.

We previously identified two lymphoid-specific proteins, RAG1 and RAG2, which collaborate to initiate these V(D)J recombination events by breaking DNA at recombination signal sequences (RSS) that flank Ig and TCR gene segments. The RAG proteins are also capable of transposing DNA, a property that could lead to such deleterious outcomes as chromosomal translocations. Recently, we developed an assay in yeast that allows us to study both recombination and transposition in a genetically tractable organism. This advance should allow us to determine what might prevent transposition from occurring in lymphoid cells and what roles DNA repair factors play in the V(D)J recombination process.

Although the same recombination machinery is responsible for assembling Ig and TCR genes, Ig segments rearrange in B cells but not T cells, Moreover, rearrangement occurs in a preferred temporal order with, for example, the Ig heavy-chain locus undergoing recombination before kappa light chain rearrangement can proceed. Developmentally controlled changes in chromatin structure appear to govern the timing of locus opening (and closing), making the antigen receptor loci ideally suited for the study of broad-scale changes in chromatin structure and the role of such alterations in governing transcription and recombination. Mapping the distribution of chromatin modifications and chromatin-associated proteins across antigen receptor loci in developing lymphocytes has allowed us to identify several novel features of chromatin structure that may lead to a molecular understanding of how recombination is regulated. For example, we find striking and tightly localized enrichments of nucleosomes flanking active TCR DJ and IgH DJ loci, in which histone H3 is dimethylated at lysine 4, but only when the loci are active. The role of these sites is one focus of our current studies.



Last Update: 8/22/2013



Publications

For a complete listing of publications click here.

 


 

Matthews, A.G., Kuo, A.J., Ramon-Maiques, S., Han, S., Champagne, K.S., Ivanov, D., Gallardo, M., Carney, D., Cheung, P., Ciccone, D.N., Walter, K.L., Utz, P.J., Shi, Y., Kutateladze, T.G., Yang, W., Gozani, O. and Oettinger, M.A. (2007) RAG2 PHD finger couples histone H3 lysine 4 trimethylation with V(D)J recombination. Nature 450:1106-1110.

Ramon-Maiques, S., Kuo, A.J., Carney, D., Matthews, A.G., Oettinger, M.A., Gozani, O. and Yang, W. (2007) The plant homeodomain finger of RAG2 recognizes histone H3 methylated at both lysine-4 and arginine-2.
Proc Natl Acad Sci U S A 104: 18993-18998.

Morshead, K. B., Ciccone, D. N., Taverna, S. D., Allis, C. D., and Oettinger, M. A. (2003). Antigen receptor loci poised for V(D)J rearrangement are broadly associated with Brg1 and flanked by peaks of histone H3 dimethylated at lysine 4.
Proc. Natl. Acad. Sci. U S A. 100:11577-11582.

Clatworthy, A. E, Valencia, M. A, Haber, J. E, and Oettinger, M. A. (2003) V(D)J recombination and RAG-mediated transposition in yeast.
Mol. Cell 12:489-499.

Elkin, S. K., Matthews, A. G., and Oettinger, M. A. (2003). The C-terminal portion of RAG2 protects against transposition in vitro.
EMBO J. 22:1931-1938.



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