Positions
- Professor
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Pathology & Immunology
Baylor College of Medicine
Houston, TX, US
- Professor
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Molecular and Cellular Biology
Baylor College of Medicine
- Professor
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Molecular Physiology and Biophysics
Baylor College of Medicine
- R. Clarence and Irene H. Fulbright Chair in Pathology
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Baylor College of Medicine
Houston, Texas, United States
- S. Donald Greenberg Chair in Pathology
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Baylor College of Medicine
Houston, Texas, United States
- Member
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Dan L Duncan Comprehensive Cancer Center
Baylor College of Medicine
Houston, Texas, United States
Addresses
- BCM-MD Anderson Hall (Lab)
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Room: BCMA-268B
Houston, TX, 77030
United States
- BCM-MD Anderson Hall (Office)
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Room: BCMA-268B
Houston, TX, 77030
United States
Education
- Fellowship at University Of California, San Francisco
- 10/1989 - San Francisco, California, United States
- Post-Doctoral Fellowship at University Of California, San Francisco
- 10/1986 - San Francisco, California, United States
- MD from Temple University School Of Medicine
- 05/1982 - Philadelphia, Pennsylvania, United States
- BS from Moravian College
- 05/1977 - Bethlehem, Pennsylvania, United States
Honors & Awards
- NIH Medical Research Trainee predoctoral award
- University of California, San Francisco (01/1981 - 12/1982)
- NIH NRSA Postdoctoral Fellowship
- University of California, San Francisco (06/1982 - 05/1985)
- Bank of America Giannini Foundation Postdoctoral Award
- University of California, San Francisco (10/1985 - 09/1986)
- March of Dimes Basil O'Connor Starter Scholar Research Award
- Baylor College of Medicine (06/1991 - 05/1994)
- Established Investigator Award, American Heart Association
- Baylor College of Medicine (07/1992 - 06/1997)
- Michael E. DeBakey, M.D. Excellence in Research Award
- Baylor College of Medicine (06/1998)
- Appointed to the S. Donald Greenberg Endowed Chair
- (05/2003)
- Michael E. DeBakey, M.D. Excellence in Research Award
- Baylor College of Medicine (04/2014)
- Appointed to the R. Clarence and Irene H. Fulbright Endowed Chair
- (09/2015)
- Steinert Award for Excellence in Myotonic Dystrophy Basic Science Research.
- Acheivement award for basic research into the mechanisms presented at the 13th International Myotonic Dystrophy Consortium Meeting held in Osaka, Japan.
- International Myotonic Dystrophy Consortium (06/2022)
- Co-chair of Post-Transcriptional Gene Regulation Gordon Research Conference
- Gordon Research Conference (07/2022)
Professional Interests
- Alternative splicing regulation in development and disease
- Molecular pathogenesis of myotonic dystrophy
- Impact of genetic variation on RNA processing
Professional Statement
At least ninety percent of human genes express multiple mRNAs by alternative splicing of their pre-mRNAs. As a result, individual genes express multiple protein isoforms which can exhibit strikingly different functions. Alternative splicing is often regulated according to cell-specific patterns based on differentiated cell type, developmental stage, or in response to an external signal. Therefore, alternative splicing not only generates an extremely diverse human proteome from a relatively small number of genes but it also directs regulated expression of these proteins in response to a wide range of cues.
We are interested in understanding the mechanisms of splicing regulation, from how regulatory proteins tell the basal machinery whether to include or skip an exon to the signaling events that coordinate splicing changes during development.
We work on two families of splicing regulators (called CELF and MBNL proteins) which regulate splicing directly by binding to specific sequence motifs within pre-mRNAs. One question being addressed is, how does binding of a positive splicing regulator recruit or stabilize binding of the basal splicing machinery? Proteins that interact with the splicing regulators, either directly or by association in an activation complex, will be identified.
A large variety of splicing changes are developmentally regulated. Another goal is to determine how the activities of the splicing regulators are modified during development and to identify the signaling pathways responsible for their modification. We are also investigating the regulatory networks responsible for coordination of developmentally regulated splicing.
A separate area of investigation is the pathogenic mechanism of myotonic dystrophy (DM1), a dominantly inherited disease caused by an expanded CTG trinucleotide repeat in the 3′ untranslated region of the DMPK gene. RNAs expressed from the expanded allele that contain long tracts of CUG repeats accumulate in the nucleus and disrupt alternative splicing. The mechanism is unknown but it involves disrupted functions of the CELF and MBNL proteins. We are using bioinformatic, biochemical, and molecular approaches to identify pre-mRNA targets of CELF and MBNL proteins whose mis-regulated splicing contributes to severe manifestations of disease. Transgenic mouse models that inducibly express CELF proteins or CUG repeat RNA are being used to investigate the mechanisms of pathogenesis and will be used to test treatment regimes.
We are interested in understanding the mechanisms of splicing regulation, from how regulatory proteins tell the basal machinery whether to include or skip an exon to the signaling events that coordinate splicing changes during development.
We work on two families of splicing regulators (called CELF and MBNL proteins) which regulate splicing directly by binding to specific sequence motifs within pre-mRNAs. One question being addressed is, how does binding of a positive splicing regulator recruit or stabilize binding of the basal splicing machinery? Proteins that interact with the splicing regulators, either directly or by association in an activation complex, will be identified.
A large variety of splicing changes are developmentally regulated. Another goal is to determine how the activities of the splicing regulators are modified during development and to identify the signaling pathways responsible for their modification. We are also investigating the regulatory networks responsible for coordination of developmentally regulated splicing.
A separate area of investigation is the pathogenic mechanism of myotonic dystrophy (DM1), a dominantly inherited disease caused by an expanded CTG trinucleotide repeat in the 3′ untranslated region of the DMPK gene. RNAs expressed from the expanded allele that contain long tracts of CUG repeats accumulate in the nucleus and disrupt alternative splicing. The mechanism is unknown but it involves disrupted functions of the CELF and MBNL proteins. We are using bioinformatic, biochemical, and molecular approaches to identify pre-mRNA targets of CELF and MBNL proteins whose mis-regulated splicing contributes to severe manifestations of disease. Transgenic mouse models that inducibly express CELF proteins or CUG repeat RNA are being used to investigate the mechanisms of pathogenesis and will be used to test treatment regimes.
Selected Publications
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Pang, P.D., Alsina, K.M., Cao, S., Koushik, A.B., Wehrens, X.H.T., Cooper, T.A. (. " CRISPR-mediated expression of the fetal Scn5a isoform in adult mice causes conduction defects and arrhythmias " J. Amer. Heart Assoc. 2018 ; 19 : e010393.
Pubmed PMID: 30371314. -
Morriss, G.R., Rajapakshe, K., Huang, S., Coarfa, C. and Cooper, T.A.. " Mechanisms of skeletal muscle wasting in a mouse model for myotonic dystrophy type 1. " Hum. Mol. Genet. 2018 ; 27 : 2789-2804.
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Singh, R.K., Kolonin, A.M., Fiorotto, M.L. and Cooper, T.A.. " Rbfox splicing factors maintain skeletal muscle mass by regulating calpain3 and proteostasis.. " Cell Reports. 2018 ; 24 : 197-208.
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Brinegar, A.E., Zheng, X., Loehr J.A., Li, W., Rodney G.G., and Cooper T.A.. " Extensive alternative splicing transitions during postnatal skeletal muscle development are required for calcium handling functions. " eLife. 2017 ; 6 : e27192.
Funding
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Transcriptome Processing Networks in Skeletal Muscle: Mechanisms and Functions
#R01AR060733 (yrs 6-10) - (03/01/2019 - 02/29/2024)
- Grant funding from NIH/NIAMS
- The long term goal of this project is to determine the extent, regulatory mechanisms, and functional consequences of transcriptome processing in adult skeletal muscle.
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Pathogenic Mechanisms and Therapeutics for the Cardiac Manifestations of Myotonic Dystrophy Type 1
#R01 HL147020 - (04/15/2019 - 03/31/2024)
- Grant funding from NIH/NHLBI
- The goals of this project are to use a heart-specific DM1 mouse model developed in the lab to identify transcriptomic and proteomic changes induced by CUGexp RNA in heart and test CRISPR/Cas9-based therapeutic approaches.
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Identification of components and mechanisms regulating expanded CUG-repeat RNP complexes in Myotonic Dystrophy Type 1 muscle cells
#R21R081472 - $275,000.00 (04/01/2023 - 03/31/2025)
- Grant funding from NIH/NIAMS
- The molecular cause of myotonic dystrophy type 1 is known to be a toxic expanded CUG-repeat RNA (CUGexp RNA) that forms ribonucleoproteins (RNPs) that localize in nuclei of skeletal muscle myofibers. The nature of the CUGexp RNP is poorly characterized. The goal of this project is to use proximity labeling to identify the protein and RNA components that contribute to the complex dynamics of the CUGexp RNA RNP and the pathological impact on skeletal muscle.
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Mechanisms of Skeletal Muscle Pathogenesis in Myotonic Dystrophy Type 1
#R01AR082852 - (09/06/2023 - 08/31/2028)
- Grant funding from NIH/NIAMS
- Myotonic dystrophy (DM) is the most common cause of adult onset muscular dystrophy and the second most common cause of muscular dystrophy overall. How the DM type 1 mutation specifically leads to muscle wasting at the molecular level is unknown. The goal of this proposal is to determine the role of CELF1 upregulation in muscle pathogenesis in combination with MBNL loss of function.
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