Repeat Expansion Diseases
We are interested in all aspects of gene regulation and how its dysregulation causes symptoms in microsatellite repeat expansion diseases. Myotonic dystrophy (dystrophia myotonica, DM) is one of these repeat expansion diseases and has served as 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 repeating RNAs cause 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.
RNA Localization and Local Translation
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.
Development of Therapeutic Approaches
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.
- Transcriptome alterations in myotonic dystrophy skeletal muscle and heart. Hum Mol Genet, 2018.
- SCA8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF3F. EMBO J, 37 (19), 2018.
- Mice with endogenous TDP-43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis. EMBO J, 37 (11), 2018.
- An engineered RNA binding protein with improved splicing regulation. Nucleic Acids Res, 46 (6): 3152-3168, 2018.
- Aberrant Myokine Signaling in Congenital Myotonic Dystrophy. Cell Rep, 21 (5): 1240-1252, 2017.
- Impeding Transcription of Expanded Microsatellite Repeats by Deactivated Cas9. Mol Cell, 68 (3): 479-490.e5, 2017.
- Antisense transcription of the myotonic dystrophy locus yields low-abundant RNAs with and without (CAG)n repeat. RNA Biol, 14 (10): 1374-1388, 2017.
- A Defective mRNA Cleavage and Polyadenylation Complex Facilitates Expansions of Transcribed (GAA)n Repeats Associated with Friedreich's Ataxia. Cell Rep, 20 (10): 2490-2500, 2017.
- A flow cytometry-based screen identifies MBNL1 modulators that rescue splicing defects in myotonic dystrophy type I. Hum Mol Genet, 26 (16): 3056-3068, 2017.
- Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy. Genes Dev, 31 (11): 1122-1133, 2017.
- Myotonic dystrophy: approach to therapy. Curr Opin Genet Dev, 44: 135-140, 2017.
- Myotonic dystrophy: disease repeat range, penetrance, age of onset, and relationship between repeat size and phenotypes. Curr Opin Genet Dev, 44: 30-37, 2017.
- Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics. Proc Natl Acad Sci U S A, 114 (8): 2060-2065, 2017.
- A Requirement for Mena, an Actin Regulator, in Local mRNA Translation in Developing Neurons. Neuron, 95 (3): 608-622.e5, 2017.
- Identification of new branch points and unconventional introns in Saccharomyces cerevisiae. RNA, 22 (10): 1522-34, 2016.
- Dose-Dependent Regulation of Alternative Splicing by MBNL Proteins Reveals Biomarkers for Myotonic Dystrophy. PLoS Genet, 12 (9): e1006316, 2016.
- Conservation of context-dependent splicing activity in distant Muscleblind homologs. Nucleic Acids Res, 44 (17): 8352-62, 2016.
- Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy. Nat Commun, 7: 11067, 2016.
- Distal Alternative Last Exons Localize mRNAs to Neural Projections. Mol Cell, 61 (6): 821-33, 2016.
- Dysregulation of mRNA Localization and Translation in Genetic Disease. J Neurosci, 36 (45): 11418-11426, 2016.
- 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.