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
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.
Sotillo Elena, Barrett David M, Black Kathryn L, Bagashev Asen, Oldridge Derek, Wu Glendon, Sussman Robyn, Lanauze Claudia, Ruella Marco, Gazzara Matthew R, Martinez Nicole M, Harrington Colleen T, Chung Elaine Y, Perazzelli Jessica, Hofmann Ted J, Maude Shannon L, Raman Pichai, Barrera Alejandro, Gill Saar, Lacey Simon F, Melenhorst Jan J, Allman David, Jacoby Elad, Fry Terry, Mackall Crystal, Barash Yoseph, Lynch Kristen W, Maris John M, Grupp Stephan A, Thomas-Tikhonenko Andrei: Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy. Cancer discovery 5(12): 1282-95, Dec 2015.
Cole Brian S, Tapescu Iulia, Allon Samuel J, Mallory Michael J, Qiu Jinsong, Lake Robert J, Fan Hua-Ying, Fu Xiang-Dong, Lynch Kristen W: Global analysis of physical and functional RNA targets of hnRNP L reveals distinct sequence and epigenetic features of repressed and enhanced exons. RNA (New York, N.Y.) 21(12): 2053-66, Dec 2015.
Martinez Nicole M, Agosto Laura, Qiu Jinsong, Mallory Michael J, Gazzara Matthew R, Barash Yoseph, Fu Xiang-Dong, Lynch Kristen W: Widespread JNK-dependent alternative splicing induces a positive feedback loop through CELF2-mediated regulation of MKK7 during T-cell activation. Genes & development 29(19): 2054-66, Oct 2015.
Yarosh Christopher A, Tapescu Iulia, Thompson Matthew G, Qiu Jinsong, Mallory Michael J, Fu Xiang-Dong, Lynch Kristen W: TRAP150 interacts with the RNA-binding domain of PSF and antagonizes splicing of numerous PSF-target genes in T cells. Nucleic acids research 43(18): 9006-16, Oct 2015.
Mallory Michael J, Allon Samuel J, Qiu Jinsong, Gazzara Matthew R, Tapescu Iulia, Martinez Nicole M, Fu Xiang-Dong, Lynch Kristen W: Induced transcription and stability of CELF2 mRNA drives widespread alternative splicing during T-cell signaling. Proceedings of the National Academy of Sciences of the United States of America 112(17): E2139-48, Apr 2015.
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Last updated: 01/21/2018
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