Kristen W. Lynch, Ph.D.
Benjamin Rush Professor of Biochemistry
Department: Biochemistry and Biophysics
Graduate Group Affiliations
Department of Biochemistry and Biophysics, Stellar-Chance Labs 909B
422 Curie Blvd
Philadelphia, PA 19104-6059
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Lynch Lab Website
RNA Group At Penn
B.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 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.
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
Slaff B, Radens CM, Jewell P, Jha A, Lahens NF, Grant GR, Thomas-Tikhonenko A, Lynch KW, Barash Y.: MOCCASIN: a method for correcting for known and unknown confounders in RNA splicing analysis. Nat Commun 12: 3353, Jun 2021.
Rivera OD, Mallory MJ, Quesnel-Vallières M, Chatrikhi R, Schultz DC, Carroll M, Barash Y, Cherry S, Lynch KW.: Alternative splicing redefines landscape of commonly mutated genes in acute myeloid leukemia. Proc Natl Acad Sci U S A 118: e2014967118, Apr 2021.
Thompson MG, Dittmar M, Mallory MJ, Bhat P, Ferretti MB, Fontoura BM, Cherry S, Lynch KW.: Viral-induced alternative splicing of host genes promotes influenza replication. Elife 9: e55500, Dec 2020.
Radens CM, Blake D, Jewell P, Barash Y, Lynch KW.: Meta-analysis of transcriptomic variation in T-cell populations reveals both variable and consistent signatures of gene expression and splicing. RNA 26: 1320-1333, October 2020.
Mallory MJ, McClory SP, Chatrikhi R, Gazzara MR, Ontiveros RJ, Lynch KW.: Reciprocal regulation of hnRNP C and CELF2 through translation and transcription tunes splicing activity in T cells. Nucleic Acids Res 48: 5710-5719, Jun 2020.
Agosto LM, Gazzara MR, Radens CM, Sidoli S, Baeza J, Garcia BA, Lynch KW.: Deep profiling and custom databases improve detection of proteoforms generated by alternative splicing. Genome Res 29: 2046-2055, December 2019.
Chatrikhi R, Mallory MJ, Gazzara MR, Agosto LM, Zhu WS, Litterman AJ, Ansel KM, Lynch KW: RNA binding protein CEFL2 regulates signal-induced alternative polyadenylation by competing with enhancers of the polyadenylation machinery. Cell Reports 28: 2795-2806, September 2019.
Black KL, Naqvi AS, Asnani M, Hayer KE, Yang SY, Gillespie E, Bagashev A, Pillai V, Tasian SK, Gazzara MR, Carroll M, Taylor D, Lynch KW, Barash Y, Thomas-Tikhonenko A.: Aberrant splicing in B-cell acute lymphoblastic leukemia. Nucleic Acids Research 47(2): 1043, January 2019.
Zhang K, Shang G, Padavannil A, Wang J, Sakthivel R, Chen X, Kim M, Thompson MG, García-Sastre A, Lynch KW, Chen ZJ, Chook YM, Fontoura BMA: Structural-functional interactions of NS1-BP protein with the splicing and mRNA export machineries for viral and host gene expression. Proceedings of the National Academy of Sciences of the US 115(52): E12218-E12227, December 2018.
McClory SP, Lynch KW, Ling JP : HnRNP L represses cryptic exons. RNA 24(6): 761-768, June 2018.