Researchers at Baylor College of Medicine identified the Rbfox2 RNA binding protein, which regulates a significant part of the alternative splicing (the process that generates multiple proteins from a single gene, playing an important role during periods of physiological change) during myogenesis (the process by which muscle cells fuse to become fibers).
The BCM team, who published its findings in the journal Molecular Cell, noted that the genes that coordinately express protein isoform transitions regulated by alternative splicing during periods of physiological change,are typically unknown, as is the functional integration of the resultant tissue-specific protein isoforms.
In their study, they reveal that the conserved Rbfox2 RNA binding protein regulates 30% of the splicing transitions observed during myogenesis. At the same time, this protein is required for the specific step of myoblast fusion. The integration of Rbfox2-dependent splicing allowed the team to identify splicing of two genes that are responsible for the fusion process. Mef2d and Rock2 were found to be Rbfox2-dependent genes important for the fusion process.
These results demonstrate that coordinated alternative splicing by a single RNA binding protein modulates transcription (Mef2d) and cell signaling (Rock2) programs to drive tissue-specific functions (cell fusion) to promote a developmental transition.
According to Dr. Thomas Cooper, the S. Donald Greenberg professor of Pathology & Immunology at Baylor and lead author of the study, researchers can only guess what is happening in this process. However, he says, they won’t really know until they can see which genes are responsible for which processes. Even so, he believes, they are now closer to “fully understanding the basic biological process for what is required for muscle function.”
Other researchers who were involved in the study include co-senior author Zheng Xia and Wei Li, both with the Department of Molecular and Cellular Biology and the NCI-designated Dan L. Duncan Cancer Center at Baylor; Christopher S. Bland, the Verna and Marrs McLean Department of Biochemistry and Molecular Biology at Baylor; Auinash Kalsotra, currently with the University of Illinois at Urbana-Champaign; Marissa A. Scavuzzo, Pathology & Immunology at Baylor; Tomaz Curk, University of Ljubljana, Slovenia; Jernej Ule, UCL Institute of Neurology, London.
Funding for the study came from: the American Heart Association (12POST11770017, 11SDG4980011); the Myotonic Dystrophy Foundation; the Ford Foundation; Baylor Research Advocates for Student Scientists (BRASS); the National Institutes of Health (R01HG007538, R01HL045565, R01AR060733, R01AR045653); and the Muscular Dystrophy Association.
This project was supported by four cores at Baylor: Cytometry and Cell Sorting Core (AI036211, CA125123, and RR024574) (Joel M. Sederstrom), the Genomic and RNA Profiling Core (Lisa D. White), Integrated Microscopy Core (HD007495, DK56338, and CA125123) (Michael Mancini), and Baculovirus/Monoclonal Antibody Facility(P30 CA125123).