The disease myotonic dystrophy (dystrophia myotonica, DM) is one of the most common form of muscular dystrophies, and is a paradigm for a class of diseases caused by toxic RNA. We are using deep sequencing technologies, such as RNA-Seq and CLIP-Seq, in combination with molecular & cell biological techniques, to better understand how the expanded microsatellite repeat in this disease leads to a myriad of symptoms in virtually all tissues of the body, including skeletal, cardiac, and smooth muscle, and also tissues of the central nervous system.
Recently, we found that the Muscleblind-like proteins (MBNLs), which are inactivated by the toxic RNA found in DM cells, also regulate the subcellular localization of many RNA species. We study how MBNL proteins can achieve these functions, and also how RNA localization is regulated at a basic level by RNA cis-elements and protein/RNA trans-factors. We aim to use both high-throughput, global approaches and high-resolution, single molecule approaches to define a "parts list" for RNA localization.
Finally, our studies of DM pathogenesis and RNA regulation are in part driven by a desire to find treatments for DM and other related diseases. We work with diverse partners in both the academic and industrial space to make progress in this area, and are taking a number of approaches to develop therapeutics that may one day enter the clinic.
- Antagonistic Regulation of mRNA Expression and Splicing by CELF and MBNL Proteins. Genome Res, 2015.
- Quantitative visualization of alternative exon expression from RNA-seq data. Bioinformatics, 2015.
- Alternative splicing regulates vesicular trafficking genes in cardiomyocytes during postnatal heart development. Nat Commun, 5: 3603, 2014.
- Muscleblind-like 1 (Mbnl1) regulates pre-mRNA alternative splicing during terminal erythropoiesis. Blood, 124 (4): 598-610, 2014.
- Genomic analysis of RNA localization. RNA Biol, 11 (8): 1040-50, 2014.
- MBNL proteins repress ES-cell-specific alternative splicing and reprogramming. Nature, 498 (7453): 241-5, 2013.
- Characterization of FUS mutations in amyotrophic lateral sclerosis using RNA-Seq. PLoS One, 8 (4): e60788, 2013.
- Skeletal muscle degenerative diseases and strategies for therapeutic muscle repair. Annu Rev Pathol, 8: 441-75, 2013.
- Design of a bioactive small molecule that targets the myotonic dystrophy type 1 RNA via an RNA motif-ligand database and chemical similarity searching. J Am Chem Soc, 134 (10): 4731-42, 2012.
- Combinatorial Mutagenesis of MBNL1 Zinc Fingers Elucidates Distinct Classes of Regulatory Events. Mol Cell Biol, 32 (20): 4155-67, 2012.
- Reduced expression of ribosomal proteins relieves microRNA-mediated repression. Mol Cell, 46 (2): 171-86, 2012.
- Transcriptome-wide Regulation of Pre-mRNA Splicing and mRNA Localization by Muscleblind Proteins. Cell, 150 (4): 710-24, 2012.
- Global regulation of alternative splicing during myogenic differentiation. Nucleic Acids Res, 38 (21): 7651-64, 2010.
- Analysis and design of RNA sequencing experiments for identifying isoform regulation. Nat Methods, 7 (12): 1009-15, 2010.
- Splice site strength-dependent activity and genetic buffering by poly-G runs. Nat Struct Mol Biol, 16 (10): 1094-100, 2009.
- An abundance of ubiquitously expressed genes revealed by tissue transcriptome sequence data. PLoS Comput Biol, 5 (12): e1000598, 2009.
- Alternative isoform regulation in human tissue transcriptomes. Nature, 456 (7221): 470-6, 2008.
- Biomechanical forces in atherosclerosis-resistant vascular regions regulate endothelial redox balance via phosphoinositol 3-kinase/Akt-dependent activation of Nrf2. Circ Res, 101 (7): 723-33, 2007.