Kristen W. Lynch, PhD
Associate Professor of Biochemistry and Biophysics
Department: Biochemistry and Biophysics
Graduate Group Affiliations
Contact information
Department of Biochemistry and Biophysics, Stellar-Chance Labs 909B
422 Curie Blvd
Philadelphia, PA 19104-6059
422 Curie Blvd
Philadelphia, PA 19104-6059
Office: 215-573-7749
Fax: 215-573-8899
Fax: 215-573-8899
Email:
klync@mail.med.upenn.edu
klync@mail.med.upenn.edu
Education:
B.A.
Harvard University, 1990.
Ph.D.
Harvard University, 1996.
Permanent linkB.A.
Harvard University, 1990.
Ph.D.
Harvard University, 1996.
Description of Research Expertise
RESEARCH INTERESTS: mechanisms of regulation of alternative splicing, antigen-induced splicing in T cellsKEY WORDS: RNA binding proteins, alternative splicing, gene regulation, T cells
DESCRIPTION OF RESEARCH:
Recent insight into the human genome has revealed that most genes encode multiple distinct protein isoforms through the process of alternative pre-mRNA splicing. My laboratory is focused on understanding the biochemical mechanisms and regulatory networks that control alternative splicing in response to antigen-challenge of the human immune system. In addition, we are working to characterize the physiological consequences of this mode of gene regulation. Recently we have identified ~150 genes that exhibit an alteration in isoform expression in response to T cell stimulation. Through our initial work on the regulated splicing of the protein tyrosine phosphatase CD45, we have identified the regulatory sequence and proteins that controls activation-induced isoform expression of CD45 as well as several other genes essential for T cell function. This work is on-going as we seek to understand the mechanism of this regulation in more molecular detail. Moreover the analysis of binding specificity of the proteins involved in signal-responsive regulation is allowing us to predict further examples of regulated splicing in the immune system. Finally, the generation of mice deficient in their expression of critical splicing regulatory proteins is allowing us to dissect the functional significance of alternative splicing for the proper function of the mammalian immune system. Together these studies are providing new insights into the mechanisms and consequences of RNA-based gene regulation in the cellular response to environmental stimuli.
ROTATION PROJECTS FOR 2009-2010:
1. Characterization of sequences that regulate alternative splicing
2. Identification of novel targets of signal-induced splicing in T cells
3. Mutational analysis of proteins that control alternative splicing
LAB PERSONNEL:
Grace Babcock, research technician
Ni-Ting Chiou, graduate student
Sarah Glenn, postdoc
Florian Heyd, postdoc
Michael Mallory, research technician
Ganesh Shankarling, postdoc
Selected Publications
Shankarling G, Lynch KW.: Minimal Functional Domains of Paralogues hnRNP L and hnRNP LL Exhibit Mechanistic Differences in Exonic Splicing Repression. Biochemical Journal May 2013.Vu NT, Park MA, Shultz JC, Goehe RW, Hoeferlin LA, Shultz MD, Smith SA, Lynch KW, Chalfant CE.: hnRNP U Enhances Caspase-9 Splicing and Is Modulated by AKT-dependent Phosphorylation of hnRNP L. The Journal of Biological Chemistry 288: 8575-8584, March 2013.
Chiou, N.; Shankarling, G. and K.W. Lynch: HnRNP L and hnRNP A1 Induce Extended U1 snRNA Interactions with an Exon to Repress Spliceosome Assembly. Molecular Cell 49: 972-982, March 2013.
Martinez Nicole M, Pan Qun, Cole Brian S, Yarosh Christopher A, Babcock Grace A, Heyd Florian, Zhu William, Ajith Sandya, Blencowe Benjamin J, Lynch Kristen W: Alternative splicing networks regulated by signaling in human T cells. RNA 18(5): 1029-40, May 2012.
Heyd Florian, Lynch Kristen W: PSF controls expression of histone variants and cellular viability in thymocytes. Biochemical and Biophysical Research Communications 414(4): 743-9, Nov 2011.
Mallory Michael J, Jackson Jason, Weber Brittany, Chi Anthony, Heyd Florian, Lynch Kristen W: Signal- and development-dependent alternative splicing of LEF1 in T cells is controlled by CELF2. Molecular and Cellular Biology 31(11): 2184-95, Jun 2011.
Motta-Mena Laura B, Smith Sarah A, Mallory Michael J, Jackson Jason, Wang Jiarong, Lynch Kristen W: A disease-associated polymorphism alters splicing of the human CD45 phosphatase gene by disrupting combinatorial repression by heterogeneous nuclear ribonucleoproteins (hnRNPs). The Journal of Biological Chemistry 286(22): 20043-53, Jun 2011.
Heyd Florian, Lynch Kristen W: Phosphorylation-dependent regulation of PSF by GSK3 controls CD45 alternative splicing. Molecular Cell 40(1): 126-37, Oct 2010.
Motta-Mena Laura B, Heyd Florian, Lynch Kristen W: Context-dependent regulatory mechanism of the splicing factor hnRNP L. Molecular Cell 37(2): 223-34, Jan 2010.
Topp, Justin D. Jackson, Jason. Melton, Alexis A. Lynch, Kristen W.: A cell-based screen for splicing regulators identifies hnRNP LL as a distinct signal-induced repressor of CD45 variable exon 4. RNA 14(10): 2038-49, Oct 2008.