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Kristen W. Lynch
4cBenjamin Rush Professor of Biochemistry
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Department: Biochemistry and Biophysics
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Graduate Group Affiliations
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Contact information
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Department of Biochemistry and Biophysics, Stellar-Chance Labs 909B
36 422 Curie Blvd
Philadelphia, PA 19104-6059
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36 422 Curie Blvd
Philadelphia, PA 19104-6059
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Office: 215-573-7749
32 Fax: 215-573-8899
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32 Fax: 215-573-8899
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Email:
klync@pennmedicine.upenn.edu
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klync@pennmedicine.upenn.edu
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Publications
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Education:
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2b Harvard University, 1990.
21 a Ph.D. c
2b Harvard University, 1996.
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21 9 B.A. c
2b Harvard University, 1990.
21 a Ph.D. c
2b Harvard University, 1996.
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Post-Graduate Training
24 5a Postdoctoral Fellow, University of California, San Francisco, 1997-2001.
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Permanent link24 5a Postdoctoral Fellow, University of California, San Francisco, 1997-2001.
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8c KEY WORDS: RNA binding proteins, alternative splicing, alternative polyadenylation, gene regulation, host-viral interaction, cancer
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20 DESCRIPTION OF RESEARCH:
5d3 Recent insight into the human genome has revealed that most genes encode multiple distinct protein isoforms through the process of alternative pre-mRNA splicing and alternative polyadenylation. My laboratory focuses on understanding the biochemical mechanisms and regulatory networks that control such RNA processing events the human immune system. We have identified multiple kinase pathways and post-transcriptional mechanisms by which the abundance and activity of RBPs are regulated in a signal-dependent manner. The lab was also one of the first to demonstrate regulation of splicing following initial recognition of splice sites; thereby expanding potential vulnerabilities for therapeutic regulation of splicing. In addition, we have identified broad programs of alternative splicing induced by antigen stimulation of T cells and by viral infection and demonstrated how these changes in gene expression control the functional response of the immune system. This work highlights the potential for treatment of infection and autoimmunity through regulation of splicing of specific genes. With regards to cancer, the Lynch lab has worked with collaborators to reveal that dysregulated splicing often phenocopies genetic mutations in leukemia. Current studies are expanding our analysis to study other mechanisms of RNA regulation, including alternative polyadenylation, translation and mRNA decay, with focus on the coordination of these processes with one another through RBPs.
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1a ROTATION PROJECTS:
2c Many rotation projects are available.
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Description of Research Expertise
79 RESEARCH INTERESTS: mechanisms and consequences of alternative RNA processing in human immune response8
8c KEY WORDS: RNA binding proteins, alternative splicing, alternative polyadenylation, gene regulation, host-viral interaction, cancer
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20 DESCRIPTION OF RESEARCH:
5d3 Recent insight into the human genome has revealed that most genes encode multiple distinct protein isoforms through the process of alternative pre-mRNA splicing and alternative polyadenylation. My laboratory focuses on understanding the biochemical mechanisms and regulatory networks that control such RNA processing events the human immune system. We have identified multiple kinase pathways and post-transcriptional mechanisms by which the abundance and activity of RBPs are regulated in a signal-dependent manner. The lab was also one of the first to demonstrate regulation of splicing following initial recognition of splice sites; thereby expanding potential vulnerabilities for therapeutic regulation of splicing. In addition, we have identified broad programs of alternative splicing induced by antigen stimulation of T cells and by viral infection and demonstrated how these changes in gene expression control the functional response of the immune system. This work highlights the potential for treatment of infection and autoimmunity through regulation of splicing of specific genes. With regards to cancer, the Lynch lab has worked with collaborators to reveal that dysregulated splicing often phenocopies genetic mutations in leukemia. Current studies are expanding our analysis to study other mechanisms of RNA regulation, including alternative polyadenylation, translation and mRNA decay, with focus on the coordination of these processes with one another through RBPs.
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1a ROTATION PROJECTS:
2c Many rotation projects are available.
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139 Burke JM, Ripin N, Ferretti MB, St Clair LA, Worden-Sapper ER, Salgado F, Sawyer SL, Perera R, Lynch KW, Parker R.: RNase L activation in the cytoplasm induces aberrant processing of mRNAs in the nucleus. PLoS Pathog 18: e1010930, Nov 2022.
e4 Blake D, Radens CM, Ferretti MB, Gazzara MR, Lynch KW.: Alternative splicing of apoptosis genes promotes human T cell survival. Elife 11: e80953, Oct 2022.
148 Basavappa MG, Ferretti M, Dittmar M, Stoute J, Sullivan MC, Whig K, Shen H, Liu KF, Schultz DC, Beiting DP, Lynch KW, Henao-Mejia J, Cherry S.: The lncRNA ALPHA specifically targets chikungunya virus to control infection. Mol Cell 82: 3729-3744, Oct 2022.
160 Peart NJ, Hwang JY, Quesnel-Vallières M, Sears MJ, Yang Y, Stoilov P, Barash Y, Park JW, Lynch KW, Carstens RP.: The global Protein-RNA interaction map of ESRP1 defines a post-transcriptional program that is essential for epithelial cell function. iScience 25: 105205, Sep 2022.
173 Gao S, Esparza M, Dehghan I, Aksenova V, Zhang K, Batten K, Ferretti MB, Begg BE, Cagatay T, Shay JW, García-Sastre A, Goldsmith EJ, Chen ZJ, Dasso M, Lynch KW, Cobb MH, Fontoura BMA.: Nuclear speckle integrity and function require TAO2 kinase. Proc Natl Acad Sci U S A 119: e2206046119, Jun 2022.
112 Jha A, Quesnel-Vallières M, Wang D, Thomas-Tikhonenko A, Lynch KW, Barash Y.: Identifying common transcriptome signatures of cancer by interpreting deep learning models. Genome Biol 23: 117, May 2022.
206 Zheng S, Gillespie E, Naqvi AS, Hayer KE, Ang Z, Torres-Diz M, Quesnel-Vallières M, Hottman DA, Bagashev A, Chukinas J, Schmidt C, Asnani M, Shraim R, Taylor DM, Rheingold SR, O'Brien MM, Singh N, Lynch KW, Ruella M, Barash Y, Tasian SK, Thomas-Tikhonenko A.: Modulation of CD22 Protein Expression in Childhood Leukemia by Pervasive Splicing Aberrations: Implications for CD22-Directed Immunotherapies. Blood Cancer Discov 3: 103-115, Mar 2022.
178 Sengupta S, West KO, Sanghvi S, Laliotis G, Agosto LM, Lynch KW, Tsichlis PN, Singh H, Patrick KL, Guerau-de-Arellano M.: PRMT5 Promotes Symmetric Dimethylation of RNA Processing Proteins and Modulates Activated T Cell Alternative Splicing and Ca(2+)/NFAT Signaling. Immunohorizons 5: 884-897, Oct 2021.
129 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.
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Selected Publications
118 Wang D, Quesnel-Vallieres M, Jewell S, Elzubeir M, Lynch K, Thomas-Tikhonenko A, Barash Y.: A Bayesian model for unsupervised detection of RNA splicing based subtypes in cancers. Nat Commun 14: 63, Jan 2023.139 Burke JM, Ripin N, Ferretti MB, St Clair LA, Worden-Sapper ER, Salgado F, Sawyer SL, Perera R, Lynch KW, Parker R.: RNase L activation in the cytoplasm induces aberrant processing of mRNAs in the nucleus. PLoS Pathog 18: e1010930, Nov 2022.
e4 Blake D, Radens CM, Ferretti MB, Gazzara MR, Lynch KW.: Alternative splicing of apoptosis genes promotes human T cell survival. Elife 11: e80953, Oct 2022.
148 Basavappa MG, Ferretti M, Dittmar M, Stoute J, Sullivan MC, Whig K, Shen H, Liu KF, Schultz DC, Beiting DP, Lynch KW, Henao-Mejia J, Cherry S.: The lncRNA ALPHA specifically targets chikungunya virus to control infection. Mol Cell 82: 3729-3744, Oct 2022.
160 Peart NJ, Hwang JY, Quesnel-Vallières M, Sears MJ, Yang Y, Stoilov P, Barash Y, Park JW, Lynch KW, Carstens RP.: The global Protein-RNA interaction map of ESRP1 defines a post-transcriptional program that is essential for epithelial cell function. iScience 25: 105205, Sep 2022.
173 Gao S, Esparza M, Dehghan I, Aksenova V, Zhang K, Batten K, Ferretti MB, Begg BE, Cagatay T, Shay JW, García-Sastre A, Goldsmith EJ, Chen ZJ, Dasso M, Lynch KW, Cobb MH, Fontoura BMA.: Nuclear speckle integrity and function require TAO2 kinase. Proc Natl Acad Sci U S A 119: e2206046119, Jun 2022.
112 Jha A, Quesnel-Vallières M, Wang D, Thomas-Tikhonenko A, Lynch KW, Barash Y.: Identifying common transcriptome signatures of cancer by interpreting deep learning models. Genome Biol 23: 117, May 2022.
206 Zheng S, Gillespie E, Naqvi AS, Hayer KE, Ang Z, Torres-Diz M, Quesnel-Vallières M, Hottman DA, Bagashev A, Chukinas J, Schmidt C, Asnani M, Shraim R, Taylor DM, Rheingold SR, O'Brien MM, Singh N, Lynch KW, Ruella M, Barash Y, Tasian SK, Thomas-Tikhonenko A.: Modulation of CD22 Protein Expression in Childhood Leukemia by Pervasive Splicing Aberrations: Implications for CD22-Directed Immunotherapies. Blood Cancer Discov 3: 103-115, Mar 2022.
178 Sengupta S, West KO, Sanghvi S, Laliotis G, Agosto LM, Lynch KW, Tsichlis PN, Singh H, Patrick KL, Guerau-de-Arellano M.: PRMT5 Promotes Symmetric Dimethylation of RNA Processing Proteins and Modulates Activated T Cell Alternative Splicing and Ca(2+)/NFAT Signaling. Immunohorizons 5: 884-897, Oct 2021.
129 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.
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