In addition to transcriptional regulation of gene output, mammalian genomes produce extensive transcriptome and proteome diversity by alternative splicing and selection of alternative 3'mRNA ends during pre-mRNA processing. As for transcription, transcriptome processing is extensively regulated in response to dynamic physiological needs. The regulation of transcriptome processing involves interconnected networks controlled by RNA binding proteins that bind to preferred sequence motifs within the pre-mRNA near the sites of regulated processing. The long term goal of this project is to determine the extent, regulatory mechanisms, and functional consequences of transcriptome processing in adult skeletal muscle. The disruption of transcriptome processing networks contributes to disease in skeletal muscle yet little is known regarding the extent or functions of normal regulation. In the first part of this proposal, we will identify the regulatory networks controlled by the Fox family of RNA binding proteins in skeletal muscle and determine their functions during myoblast differentiation. We will use tissue specific and inducible knock outs of the two Fox genes expressed in skeletal muscle to determine the functions of the regulatory networks in myofibers and satellite cells in adult skeletal muscle. In the second part of the proposal, we will identify additional regulatory networks operative during myoblast differentiation using a bichromatic splicing reporter in high throughput RNAi screens. Knowledge gained will be directed toward understanding the roles of these networks in adult skeletal muscle. The results will provide a new understanding of the role of nuclear post-transcriptional regulation in the diverse homeostatic functions of adult skeletal muscle and its capacity for repair. This understanding is important for development and application of novel therapeutic strategies to conditions that negatively affect skeletal muscle function.

Public Health Relevance

Post-transcriptional regulation of gene expression, such as alternative splicing and 3'end processing, play a large role in controlling gene expression. This proposal studies the mechanisms of alternative splicing and 3'end processing during skeletal muscle differentiation and in adult skeletal muscle tissue. This information will be used to understand normal processes in skeletal muscle useful for future development of therapeutic approaches to reverse or circumvent disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR060733-03
Application #
8447506
Study Section
Special Emphasis Panel (ZRG1-MOSS-K (02))
Program Officer
Boyce, Amanda T
Project Start
2011-04-01
Project End
2016-02-29
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
3
Fiscal Year
2013
Total Cost
$334,519
Indirect Cost
$120,769
Name
Baylor College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Giudice, Jimena; Loehr, James A; Rodney, George G et al. (2016) Alternative Splicing of Four Trafficking Genes Regulates Myofiber Structure and Skeletal Muscle Physiology. Cell Rep 17:1923-1933
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Pedrotti, Simona; Giudice, Jimena; Dagnino-Acosta, Adan et al. (2015) The RNA-binding protein Rbfox1 regulates splicing required for skeletal muscle structure and function. Hum Mol Genet 24:2360-74
Hsu, Tiffany Y-T; Simon, Lukas M; Neill, Nicholas J et al. (2015) The spliceosome is a therapeutic vulnerability in MYC-driven cancer. Nature 525:384-8
Jaiswal, Manish; Haelterman, Nele A; Sandoval, Hector et al. (2015) Impaired Mitochondrial Energy Production Causes Light-Induced Photoreceptor Degeneration Independent of Oxidative Stress. PLoS Biol 13:e1002197
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Kalsotra, Auinash; Singh, Ravi K; Gurha, Priyatansh et al. (2014) The Mef2 transcription network is disrupted in myotonic dystrophy heart tissue, dramatically altering miRNA and mRNA expression. Cell Rep 6:336-45

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