We are interested in gene regulation in lymphocytes. Immunoglobulin heavy chain (IgH) and T cell receptor chain (TCR ) genes are used as probes of early B and T cell differentiation, respectively. These genes share several common features such as assembly by two independently-regulated recombination events, susceptibility to feedback inhibition (allelic exclusion), and requirement for tissue-specific enhancers to activate transcription of the recombined gene. Presumably, cues provided by the bone marrow, or thymus, direct lineage-specific gene expression. Our goal is to understand the molecular details of this process. For example, what are the crucial regulatory sequences and what proteins interact with these sequences? How do combinations of proteins activate enhancers and silencers? How do these proteins alter chromatin structure and how is the altered structure propagated? How does the microenvironment influence differentiation stage-specific gene expression? These objectives are addressed by a combination of genetic and biochemical approaches (1-4).

We also study lymphocyte activation from the perspective provided by the transcription factor NF-κB. We previously showed that NF-κB proteins are in nucleo-cytoplasmic flux mediated by nuclear import and export sequences in Rel proteins and IκB (5,6). Our current interest is to investigate the functional consequences of NF-κB/IκB shuttling. Towards this objective, we are studying active and "passive" cell death in lymphocytes, and the role of NF-κB in linking innate and adaptive immune responses via generalized inflammation.

Ishii H., R. Sen and M.J.Pazin. (2004) Combinatorial control of DNase I-hypersensitive site formation and erasure by immunoglobulin heavy chain enhancer-binding proteins. J. Biol. Chem. 99(2):399-408 [PubMed]

Chowdhury D, and Sen R. (2004) Mechanisms for feedback inhibition of the immunoglobulin heavy chain locus. Current Opinion in Immunology 7(6):827-38 [PubMed]

Hesslein D.G.T., D.L. Pflugh, D. Chowdhury, A.L.M.Bothwell, R. Sen and D.G.Schatz. (2003) Pax5 is required for recombination of transcribed, acetylated, 5’ IgH V gene segments. Genes and Dev. 117(3):239-54 [PubMed]

Chowdhury D. and R. Sen. (2003) Transient IL-7/IL-7R signaling provides a mechanism for feedback inhibition of immunoglobulin heavy chain gene rearrangements. Immunity 62(1):80-8 [PubMed]

Tam WF and Sen R. (2001) IkB family members function by different mechanisms. J. Biol. Chem. 364(9429):163-71 [PubMed]

Tam W.F., W. Wang and R. Sen. (2001) Cell-specific association and shuttling of IkBa provides a mechanism for nuclear NF-kB in B lymphocytes. Mol Cell Biol. 14(11):1089-105 [PubMed]