Positions

Professor
Pathology & Immunology
Baylor College of Medicine
Houston, TX, US
Professor
Molecular and Cellular Biology
Baylor College of Medicine
Professor
Molecular Physiology and Biophysics
Baylor College of Medicine
R. Clarence and Irene H. Fulbright Chair in Pathology
Baylor College of Medicine
Houston, Texas, United States
S. Donald Greenberg Chair in Pathology
Baylor College of Medicine
Houston, Texas, United States
Member
Dan L Duncan Comprehensive Cancer Center
Baylor College of Medicine
Houston, Texas, United States

Education

Fellowship at University Of California, San Francisco
Post-Doctoral Fellowship at University Of California, San Francisco
MD from Temple University School Of Medicine
BS from Moravian College

Honors & Awards

NIH Medical Research Trainee predoctoral award
NIH NRSA Postdoctoral Fellowship
Bank of America Giannini Foundation Postdoctoral Award
March of Dimes Basil O'Connor Starter Scholar Research Award
Established Investigator Award, American Heart Association
Michael E. DeBakey, M.D. Excellence in Research Award
Appointed to the S. Donald Greenberg Endowed Chair
Michael E. DeBakey, M.D. Excellence in Research Award
Appointed to the R. Clarence and Irene H. Fulbright Endowed Chair

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.

Selected Publications

Funding

Molecular Pathogenesis of Myotonic Dystrophy
- #R01AR045653 (yrs 16-20)
Grant funding from NIH/NIAMS
The objectives are to determine the basis for toxicity of CUG RNA repeats in myotonic dystrophy.
Troponin T Alternative Splicing In Embryonic Heart
- #R01HL045565 (yrs. 22-26)
Grant funding from NIH/NHLBI
The goals of this project are to define the splicing regulatory networks of CELF and MBNL proteins during mammalian postnatal heart development then identify and experimentally demonstrate the physiological roles of a select group of CELF1 and/or MBNL1-regulated postnatal alternative splicing transitions.
Transcriptome Processing Networks in Skeletal Muscle: Mechanisms and Functions
- #R01AR060733 (yrs 1-5)
Grant funding from NIH/NIAMS
The goal of this project is to determine the extent, regulatory mechanisms, and functional consequences of transcriptome processing in adult skeletal muscle and the role of Rbfox proteins in adult muscle myofibers and stem cells.