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Tom Cooper

Thomas A. Cooper

E-mail: tcooper@bcm.edu

Professor, Baylor College of Medicine

B.S., Moravian College, Bethlehem, PA, 1977
M.D., Temple University Medical School, Philadelphia, 1982
Postdoc, University of California, San Francisco, 1982-86

Alternative splicing regulation in development and disease

Up to seventy six 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.

Selected Publications

Kalsotra A, Xiao X, Ward AJ, Castle JC, Johnson JM, Burge CB, Cooper TA (2008) A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart. Proceedings of the National Academy of Sciences USA 105:20333-20338.

Wang GS, Kuyumcu-Martinez MN, Sarma S, Mathur N, Wehrens XH, Cooper TA (2009) PKC inhibition ameliorates the cardiac phenotype in a mouse model of myotonic dystrophy type 1. Journal of Clinical Investigation 119:3797-3806.

Goo YH, Cooper TA (2009) CUGBP2 directly interacts with U2 17S snRNP components and promotes U2 snRNA binding to cardiac troponin T pre-mRNA. Nucleic Acids Research 37:4275-4286.

Bland CS, Wang ET, Vu A, David MP, Castle JC, Johnson JM, Burge CB, Cooper TA (2010) Global regulation of alternative splicing during myogenic differentiation. Nucleic Acids Research 38:7651-7664.

Kalsotra A, Wang K, Li PF, Cooper TA (2010) MicroRNAs coordinate an alternative splicing network during mouse postnatal heart development. Genes & Development 24:653-658.

Koshelev M, Sarma S, Price RE, Wehrens XH, Cooper TA (2010) Heart-specific overexpression of CUGBP1 reproduces functional and molecular abnormalities of myotonic dystrophy type 1. Human Molecular Genetics 19:1066-1075.

Ward AJ, Rimer M, Killian JM, Dowling JJ, Cooper TA (2010) CUGBP1 overexpression in mouse skeletal muscle reproduces features of myotonic dystrophy type 1. Human Molecular Genetics 19:3614-3622.

Grammatikakis I, Goo YH, Echeverria GV, Cooper TA (2011) Identification of MBNL1 and MBNL3 domains required for splicing activation and repression. Nucleic Acids Research 39:2769-2780.

Lee JE, Bennett CF, Cooper TA (2012) RNase H-mediated degradation of toxic RNA in myotonic dystrophy type 1. Proceedings of the National Academy of Sciences USA 109:4221-4226.

Contact Information

Thomas A Cooper, M.D.
Department of Molecular and Cellular Biology
Baylor College of Medicine
One Baylor Plaza, Cullen 268B
Houston, Texas 77030, U.S.A.

Tel: (713) 798-3141
Fax: (713) 798-5838
E-mail: tcooper@bcm.edu

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