The recent sequencing and analysis of the human genome has made it strikingly apparent that most individual genes encode multiple distinct protein isoforms, through the process of alternative pre-mRNA splicing. As alternate isoforms of a given gene often exert opposing activities within the cell, understanding how the expression of each isoform is regulated is critical to understanding how cellular functions are controlled.
My laboratory is focused on understanding the biochemical mechanisms and regulatory networks that control alternative splicing in response to changes in the extracellular environment. In particular, we are interested in the role of signal-induced splicing within the mammalian immune system. Cells of the adaptive immune system must undergo significant and precise changes in response to antigen challenge. Recently we have determined that upwards of 10-20% of spliced genes exhibit an alteration in isoform expression in response to T cell stimulation. Moreover, in cases in which the function of alternative isoforms has been studied, it is clear that mis-regulation of splicing in the immune system is a common contributor to autoimmune disease. Thus, elucidation of the regulation of activation-induced splicing in T cells will contribute both to our understanding of the basic chemistry of splicing as well as to our understanding of the molecular basis of human disease.
In recent years work in our lab has focused on the regulated splicing of the protein tyrosine phosphatase, CD45. This has led to the identification of a exonic splicing regulatory sequence that controls the signal-induced repression of the CD45 variable exons as well as exons in other genes essential for T cell function. We have further identified the proteins that confer splicing regulation through this sequence element, and the novel mechanisms by which this regulation occurs. We are continuing our investigation to further delineate how antigen signaling through the T cell receptor alters the activity of the CD45 splicing regulatory proteins. In addition, we are now expanding our studies to include additional networks of co-regulated splicing events in T cells that will yield new insights into the mechanisms and consequences of RNA-based gene regulation in the cellular response to environmental stimuli.
RESEARCH INTERESTS
RNA-based gene regulation
pre-mRNA splicing
alternative splicing
T cell activation
gene regulation in the immune system
RECENT PUBLICATIONS
Melton, A.A., J. Jackson, J. Wang and K.W. Lynch, "Combinatorial control of signal-induced exon repression by HnRNP L and PSF" Mol Cell Biol., in press 2007
Ip, J., A. Tong, Q. Pan, J. Topp, B.J. Blencowe and K.W. Lynch, "Global analysis of alternative splicing during T cell activation" RNA, 13:563-572, 2007
Rothrock, C.R., A.E. House and K.W. Lynch, "HnRNP L represses exon splicing via a regulated exonic splicing silencer" EMBO J, 24:2792-2802, 2005
Rothrock, C., B. Cannon, B. Hahm and K.W. Lynch, "A conserved signal-responsive sequence mediates activation-induced alternative splicing of CD45." Mol. Cell, 12:1317-1324, 2003
SIGNIFICANT PUBLICATIONS
Lynch, K. W., "Consequences of regulated pre-mRNA splicing in the immune system." Nat. Rev. Immunol., 4:931-940, 2004
Tong, A., J. Nguyen and K.W. Lynch, "Differential expression of CD45 isoforms is controlled by the combined activity of basal and inducible splicing regulatory elements in each of the variable exons" J. Biol. Chem., 280:38297-304, 2005
Lynch, K.W., and Weiss, A., "A CD45 polymorphism associated with multiple sclerosis disrupts an exonic splicing silencer." J. Biol. Chem., 276:24341-24347, 2001
Lynch, K.W., and Weiss, A., "A model system for activation-induced alternative splicing of CD45 pre-mRNA in T cells implicates protein kinase C and Ras." Mol. Cell Biol., 20:70-80, 2000
Hertel, K.J., Lynch, K.W., and Maniatis, T., "Common themes in the function of transcription and splicing enhancers." Curr. Opin. Cell Biol., 9:350-357, 1997
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