HNRNPA1-induced spliceopathy in a transgenic mouse model of myotonic dystrophy
Open Access
- 10 March 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (10), 5472-5477
- https://doi.org/10.1073/pnas.1907297117
Abstract
Studies on myotonic dystrophy type 1 (DM1) have led to the RNA-mediated disease model for hereditary disorders caused by non-coding microsatellite expansions. This model proposes that DM1 disease manifestations are caused by a reversion to fetal RNA processing patterns in adult tissues due to the expression of toxic CUG RNA expansions (CUG(exp)) leading to decreased muscleblind-like, but increased CUGBP1/ETR3-like factor 1 (CELF1), alternative splicing activities. Here, we test this model in vivo, using the mouse HSA(LR) poly(CUG) model for DM1 and recombinant adeno-associated virus (rAAV)-mediated transduction of specific splicing factors. Surprisingly, systemic overexpression of HNRNPA1, not previously linked to DM1, also shifted DM1-relevant splicing targets to fetal isoforms, resulting in more severe muscle weakness/myopathy as early as 4 to 6 wk posttransduction, whereas rAAV controls were unaffected. Overexpression of HNRNPA1 promotes fetal exon inclusion of representative DM1-relevant splicing targets in differentiated myoblasts, and HITS-CLIP of rAAV-mycHnrnpa1-injected muscle revealed direct interactions of HNRNPA1 with these targets in vivo. Similar to CELF1, HNRNPA1 protein levels decrease during postnatal development, but are elevated in both regenerating mouse muscle and DM1 skeletal muscle. Our studies suggest that CUG exP RNA triggers abnormal expression of multiple nuclear RNA binding proteins, including CELF1 and HNRNPA1, that antagonize MBNL activity to promote fetal splicing patterns.Funding Information
- National Natural Science Foundation of China (31771592)
- National Natural Science Foundation of China (31401107)
- China Postdoctoral Science Foundation (2015T80476)
- China Postdoctoral Science Foundation (2014M560369)
- HHS | National Institutes of Health (R01AR046799)
- HHS | National Institutes of Health (P01NS058901)
This publication has 52 references indexed in Scilit:
- RNA-binding proteins in microsatellite expansion disorders: Mediators of RNA toxicityBrain Research, 2012
- Cholinergic‐associated loss of hnRNP‐A/B in Alzheimer's disease impairs cortical splicing and cognitive function in miceEMBO Molecular Medicine, 2012
- Integrative Genome-wide Analysis Reveals Cooperative Regulation of Alternative Splicing by hnRNP ProteinsCell Reports, 2012
- Preclinical Differences of Intravascular AAV9 Delivery to Neurons and Glia: A Comparative Study of Adult Mice and Nonhuman PrimatesMolecular Therapy, 2011
- TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNANature, 2011
- Antagonistic role of hnRNP A1 and KSRP in the regulation of let-7a biogenesisNature Structural & Molecular Biology, 2010
- Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophyNature Structural & Molecular Biology, 2010
- Increased Steady-State Levels of CUGBP1 in Myotonic Dystrophy 1 Are Due to PKC-Mediated HyperphosphorylationMolecular Cell, 2007
- The multifunctional RNA-binding protein hnRNP A1 is required for processing of miR-18aNature Structural & Molecular Biology, 2007
- Dynamic balance between activation and repression regulates pre‐mRNA alternative splicing during heart developmentDevelopmental Dynamics, 2005