Faculty Research Page

Mark S. Schlissel

Mark Schlissel

Professor of Immunology and Pathogenesis*
*And Affiliate, Division of Biochemistry and Molecular Biology

Lab Homepage: http://mcb.berkeley.edu/labs/schlissel/

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Research Interests

The Regulation of Antigen Receptor Gene Rearrangement and Lymphocyte Development. Immunoglobulin (Ig) and T cell receptor (TCR) genes are assembled during lymphocyte development by a novel series of highly regulated DNA rearrangement reactions known as V(D)J recombination. Understanding the regulation of gene rearrangement is important because its products (Ig and TCR molecules) control the development and function of B and T cells and because errors in the process can result in leukemia, lymphoma, or immunodeficiency disease. A single enzyme complex known as the V(D)J recombinase is required for the rearrangement of each of the seven complex genetic loci encoding antigen receptor chains. The recombinase recognizes a highly conserved DNA sequence, the RSS. Our data suggests that transcription or transcription factor binding targets the recombination reaction to a particular genetic locus at the appropriate stage of development. My lab is interested in determining the molecular basis of this link between transcription and gene rearrangement during B cell development. In addition, we are interested in the reaction mechanism of the V(D)J recombinase and the involvement of V(D)J recombination in the origin of lymphoid malignancies including leukemia and lymphoma.

Using bone marrow, thymus and fetal liver from wild-type or recombination-deficient Ig or TCR transgenic mice, we have purified primary lymphoid cells "frozen" at different stages of development. We are analyzing signal transduction pathways, patterns of transcription factor activity and chromosomal DNA-protein interactions to determine the critical receptors, protein factors and DNA sequences involved in the regulation of B and T cell development and Ig and TCR gene rearrangement. We have also devised a series of novel assays which detect recombination reaction intermediates and are using them to study both the developmental regulation and reaction mechanism of the V(D)J recombinase. Recently, we devised an in vitro assay system which recapitulates the developmental regulation of V(D)J recombination and are engaged in the dissection of its molecular components. Additional interests pursued through the above studies include the role of chromatin structure in the regulation of gene activity, the mechanisms of transcriptional enhancer activity, and the biochemistry of cell transformation.

The origins of acute lymphocytic leukemia.  Oncogenes are mutant versions of normal cellular genes. One such gene, v-Abl, encodes a fusion between retroviral gag and the cellular proto-oncogene c-Abl. Mice infected with a v-Abl-expressing retrovirus develop acute lymphocytic leukemia. Various human leukemias are associated with chromosomal translocations involving the human homologue of this gene. We are interested in understanding at the molecular level the normal function of the c-Abl proto-oncogene in lymphocyte development and how the mutant version of this gene causes leukemia.

Current Projects

Active projects in the lab include 1) an analysis of the influence of chromatin structure on the targeting of V(D)J recombination; 2) promoter and enhancer activities involved in the transcriptional regulation of genes encoding the V(D)J recombinase (RAG1 and RAG2); 3) retroviral cDNA library screens for regulators of B cell development; 4) the use of gene targeting to determine the function of various domains of RAG1 and RAG2; 5) identifying transcription factors and DNA sequences involved in the regulated activation of rearrangement at the Ig kappa locus and TCR beta locus; 6) determining the role of transcriptional enhancer sequences in the targeting of recombination and in coding joint formation; 7) elucidating the rules governing receptor editing; 8) studying the mechanism and determining the frequency of transposition events catalyzed by the recombinase during lymphocyte development; 9) determining the biological function of the proto-oncogene c-Abl in developing B cells; and 10) determining the mechanisms by which the viral oncogene v-Abl arrests B cell development and causes pre-B cell leukemia; 11) probing the role of specific miRNAs in B cell development and leukemia.

Selected Publications

NF-{kappa}B activity marks cells engaged in receptor editing. [Cadera, E.J., Wan, F., Amin, R.H., Nolla, H., Lenardo, M.J., and Schlissel, M.S. (2009) J. Exp. Med. 206, 1803-1816]

The effects of c-Abl mutation on developing B cell differentiation and survival. [Brightbill, H., and Schlissel, M.S. (2009) Int. Immunol. 21, 575-585]

Biallelic, ubiquitous transcription from the distal germline Ig{kappa} locus promoter during B cell development. [Amin, R.H., Cado, D., Nolla, H., Huang, D., Shinton, S.A., Zhou, Y., Hardy, R.R., and Schlissel, M.S. (2009) Proc. Natl. Acad. Sci. USA 106, 522-527]

Foxo1 directly regulates the transcription of recombination-activating genes during B cell development. [Amin, R.H., Schlissel, M.S. (2008)  Nat Immunol 9, 613-622]

Association between the Igk and Igh immunoglobulin loci mediated by the 3' Igk enhancer induces 'decontraction' of the Igh locus in pre-B cells. [Hewitt, S.L., Farmer, D., Marszalek, K., Cadera, E., Liang, H.E., Xu, Y., Schlissel, M.S., Skok, J.A. (2008) Nat Immunol 9, 396-404]

Chromosomal position of a VH gene segment determines its activation and inactivation as a substrate for V(D)J recombination. [Bates, J.G., Cado, D., Nolla, H. & Schlissel, M.S. (2007)  J Exp Med 204, 3247-3256]

Chromosomal reinsertion of broken RSS ends during T cell development. [Curry, J.D., D. Schulz, C.J. Guidos, J.S. Danska, L. Nutter, A. Nussenzweig, and M.S. Schlissel. (2007)  J Exp Med 204:2293-2303] 

Leukemia and lymphoma: a cost of doing business for adaptive immunity. [M.S. Schlissel, C.R. Kaffer, and J.D. Curry (2006) Genes Dev 20, 1539-1544]

Single-strand recombination signal sequence nicks in vivo: evidence for a capture model of synapsis. [J.D. Curry, J.K. Geier, J.K., and M.S. Schlissel  (2005) Nat Immunol 6, 1272-1279]

Variegated transcriptional activation of the immunoglobulin k locus in pre-B cells contributes to the allelic exclusion of light-chain expression. [H.E. Liang, L.Y. Hsu, D. Cado, and M.S. Schlissel (2004) Cell 118, 19-29]

Pax5 activates immunoglobulin heavy chain V-to-DJ rearrangement in transgenic thymocytes. [L.-Y. Hsu, H.E. Liang, K. Johnson, C. Kang, and M.S. Schlissel (2004) J Exp Med 199, 825-830]

A conserved transcriptional enhancer regulates RAG gene expression in developing B cells. [L.-Y. Hsu, J. Lauring, H.E. Liang, S. Greenbaum, D. Cado, Y. Zhuang, and M.S. Schlissel (2003) Immunity 19, 105-117]

A small molecule Abl knase inhibitor induces differentiation of Abelson virus-transformed pre-B cell lines. [S. A. Muljo and M. S. Schlissel (2003) Nat Immunol 4, 31-37]

The "dispensable" portion of RAG2 is necessary for efficient V-to-DJ rearrangement during B and T cell development [H. E. Liang, L. Y. Hsu, D. Cado, L. G. Cowell, G. Kelsoe, and M. S. Schlissel (2002) Immunity 17, 639-651]

Last Updated 2010-07-16