Kristen W. Lynch

faculty photo
Professor of Biochemistry and Biophysics
Department: Biochemistry and Biophysics

Contact information
Department of Biochemistry and Biophysics, Stellar-Chance Labs 909B
422 Curie Blvd
Philadelphia, PA 19104-6059
Office: 215-573-7749
Fax: 215-573-8899
Education:
B.A.
Harvard University, 1990.
Ph.D.
Harvard University, 1996.
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Description of Research Expertise

RESEARCH INTERESTS: mechanisms of regulation of alternative splicing, antigen-induced splicing in T cells


KEY 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:
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

Selected Publications

Motta-Mena, L.B.; Reade A.; Mallory, M.J.; Glantz, S.; Weiner, O.D.; Lynch, K.W. and K.H. Gardner: An optogenetic gene expression system with rapid activation and deactivation kinetics. Nature Chemical Biology Jan 2014.

Shankarling Ganesh, Cole Brian S, Mallory Michael J, Lynch Kristen W: Transcriptome-Wide RNA Interaction Profiling Reveals Physical and Functional Targets of hnRNP L in Human T Cells. Molecular and Cellular Biology 34(1): 71-83, Jan 2014.

Gazzara Matthew R, Vaquero-Garcia Jorge, Lynch Kristen W, Barash Yoseph: In silico to in vivo splicing analysis using splicing code models. Methods (San Diego, Calif.) Dec 2013.

Smith Sarah A, Ray Debashish, Cook Kate B, Mallory Michael J, Hughes Timothy R, Lynch Kristen W: Paralogs hnRNP L and hnRNP LL exhibit overlapping but distinct RNA binding constraints. PloS one 8(11): e80701, November 2013.

Ray Debashish, Kazan Hilal, Cook Kate B, Weirauch Matthew T, Najafabadi Hamed S, Li Xiao, Gueroussov Serge, Albu Mihai, Zheng Hong, Yang Ally, Na Hong, Irimia Manuel, Matzat Leah H, Dale Ryan K, Smith Sarah A, Yarosh Christopher A, Kelly Seth M, Nabet Behnam, Mecenas Desirea, Li Weimin, Laishram Rakesh S, Qiao Mei, Lipshitz Howard D, Piano Fabio, Corbett Anita H, Carstens Russ P, Frey Brendan J, Anderson Richard A, Lynch Kristen W, Penalva Luiz O F, Lei Elissa P, Fraser Andrew G, Blencowe Benjamin J, Morris Quaid D, Hughes Timothy R: A compendium of RNA-binding motifs for decoding gene regulation. Nature 499(7457): 172-7, Jul 2013.

Tsai Pei-Ling, Chiou Ni-Ting, Kuss Sharon, García-Sastre Adolfo, Lynch Kristen W, Fontoura Beatriz M A: Cellular RNA binding proteins NS1-BP and hnRNP K regulate influenza A virus RNA splicing. PLoS pathogens 9(6): e1003460, Jun 2013.

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.

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Last updated: 09/08/2014
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