Kristen W. Lynch, PhD
422 Curie Blvd
Philadelphia, PA 19104-6059
Harvard University, 1990.
Harvard University, 1996.
Description of Research ExpertiseRESEARCH 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
Selected PublicationsChatrikhi 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.
Thompson MG, Muñoz-Moreno R, Bhat P, Roytenberg R, Lindberg J, Gazzara MR, Mallory MJ, Zhang Ke, García-Sastre A, Fontoura BMA, Lynch KW: Co-Regulatory Activity of hnRNP K and NS1-BP in Influenza and Human mRNA Splicing. Nature Communications 9(1): 2407, June 2018.
Shinde Mansi Y, Sidoli Simone, Kulej Katarzyna, Mallory Michael J, Radens Caleb M, Reicherter Amanda L, Myers Rebecca L, Barash Yoseph, Lynch Kristen W, Garcia Benjamin A, Klein Peter S: Phosphoproteomics reveals that glycogen synthase kinase-3 phosphorylates multiple splicing factors and is associated with alternative splicing. The Journal of biological chemistry 292(44): 18240-18255, Nov 2017.
Gazzara Matthew R, Mallory Michael J, Roytenberg Renat, Lindberg John P, Jha Anupama, Lynch Kristen W, Barash Yoseph: Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes. Genome research 27(8): 1360-1370, Aug 2017.
Ajith Sandya, Gazzara Matthew R, Cole Brian S, Shankarling Ganesh, Martinez Nicole M, Mallory Michael J, Lynch Kristen W: Position-dependent activity of CELF2 in the regulation of splicing and implications for signal-responsive regulation in T cells. RNA biology 13(6): 569-81, Jun 2016.
Mor Amir, White Alexander, Zhang Ke, Thompson Matthew, Esparza Matthew, Muñoz-Moreno Raquel, Koide Kazunori, Lynch Kristen W, García-Sastre Adolfo, Fontoura Beatriz M A: Influenza virus mRNA trafficking through host nuclear speckles. Nature Microbiology 1(7): 16069, May 2016.
Vaquero-Garcia Jorge, Barrera Alejandro, Gazzara Matthew R, González-Vallinas Juan, Lahens Nicholas F, Hogenesch John B, Lynch Kristen W, Barash Yoseph: A new view of transcriptome complexity and regulation through the lens of local splicing variations. eLife 5: e11752, Feb 2016.