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
Ho TH, Charlet-B N, Poulos MG, Singh G, Swanson MS, Cooper TA (2004) Muscleblind proteins regulate alternative splicing. EMBO
Journal 23:3103-3112.
Cooper TA (2005) Alternative splicing regulation impacts heart development. Cell 120:1-2.
Han J, Cooper TA (2005) Identification of CELF splicing activation and repression domains in vivo. Nucleic Acids Research 33:2769-2780.
Ladd AN, Taffet G, Hartley C, Kearney DL, Cooper TA (2005) Cardiac tissue-specific repression of CELF activity disrupts alternative splicing and
causes cardiomyopathy. Molecular and Cellular Biology 25:6267-6278.
Cooper TA (2006) A reversal of misfortune for myotonic dystrophy? New England Journal of Medicine 355:1825-1827.
Ranum LP, Cooper TA (2006) RNA-mediated neuromuscular disorders. Annual Review of Neuroscience 29:259-277.
Bland CS, Cooper TA (2007) Micromanaging alternative splicing during muscle differentiation. Developmental Cell 12:171-172.
Wang GS, Kearney DL, De Biasi M, Taffet G, Cooper TA (2007) Elevation of RNA-binding protein CUGBP1 is an early event in an inducible heart-
specific mouse model of myotonic dystrophy. Journal of Clinical Investigation 117:2802-2811.
Wang GS, Cooper TA (2007) Splicing in disease: disruption of the splicing code and the decoding machinery. Nature Reviews Genetics 8:749-761.
Kuyumcu-Martinez NM, Wang GS, Cooper TA (2007) Increased steady-state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC-mediated
hyperphosphorylation. Molecular Cell 28:68-78.
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.tmc.edu
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