Mariano Agustin Garcia-Blanco
Charles D. Watts Professor of Molecular Genetics and Microbiology
In the great majority of human transcripts coding information is found in short exons that are identified and ligated together in the process known as pre-messenger RNA splicing. The complex nature of genes provides for versatility of expression because one gene can encode for many proteins by altering the selection of exons to be included in the messenger. This process is known as alternative splicing and it is the major engine of proteome diversity in humans. Alternative splicing is tightly regulated in normal development and is deregulated in disease. The evolution of alternative splicing probably accounts for the possibility to maintain a limited number of genes while increasing tissue diversity.
The importance of connections between RNA processing and synthesis (transcription) has recently come to light. The molecular nature of these connections remains unresolved. The laboratory investigates these connections, physical and functional, between RNA polymerase II transcript elongation and alternative splicing. This work is focused on a protein found to be a repressor of HIV-1 transcription elongation, CA150. CA150 appears to physically and functionally link the elongating RNAP II complex with the splicing machinery.
My laboratory also studies the regulation of processing of messenger RNAs focusing on the alternative splicing of the fibroblast growth factor receptor-2 (FGFR2) transcripts. FGFR2 transcripts are alternatively spliced to yield regulated expression of two receptors with dramatically different ligand specificity. Not only is this process critical for normal development of many epithelial tissues, but also during progression of prostate tumors the alternative splicing of FGFR2 is abnormal. We have characterized the cis-elements responsible for regulation of alternative splicing in FGFR2 and some of the trans-acting factors that control this process. In the last two years we have identified two critical trans-acting factors, the exon repressor PTB and the activator FXH. We have also developed novel reporters that will assay the alternative splicing of FGFR2 in tissues and tumors in living cells and animals. Finally we are also investigating the networks that globally determine alternative splicing of large classes of gene products. We are doing this with a combination of depletion by RNA interference and complementation together with en masse analysis using microarrays.
Finally the laboratory has recently begun a study of the RNA-protein interactions that dictate gene expression in two families of pathogenic flaviviruses, yellow fever virus (YFV) and dengue viruses (DV). These agents are major health risks in the tropics and represent an emerging danger to the US population. This threat was announced by the West Nile virus epidemic, caused by a highly related flavivirus. Little is known about the molecular biology of YFV and DV, and my laboratory is applying tools and methods we have developed to study human gene expression to shed light into critical functions of these important pathogens.
Appointments and Affiliations
- Charles D. Watts Professor of Molecular Genetics and Microbiology
- Adjunct Professor in the Molecular Genetics and Microbiology
- Director, Center for RNA Biology
- Office Phone: (919) 613-8636
- Email Address: email@example.com
- Ph.D. Yale University, 1988
- M.D. Yale University, 1984
- B.A. Harvard University, 1977
Awards, Honors, and Distinctions:
- AAAS Fellows. American Association for the Advancement of Science, The. 2011
- MGM 293: Research Independent Study I
- MGM 593: Research Independent Study
In the News:
- New Gene Interaction Appears to be Associated with Increased MS Risk (Mar 23, 2017 | Duke Health News )
- Duke-NUS researchers shed more light on how dengue gets its bite (Jul 16, 2014 | Singapore Today )