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HNRNPA1-induced spliceopathy in a transgenic mouse model of myotonic dystrophy.

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机构： [1]School of Life Science and Technology, The Key Laboratory of Developmental Genes and Human Disease, Southeast University, 210096 Nanjing, China [2]Department of Molecular Genetics and Microbiology, Genetics Institute and the Center for NeuroGenetics, University of Florida, College of Medicine, Gainesville, FL 32610 [3]Jiangsu Co-innovation Center of Neuroregeneration, Nantong University, 226001 Nantong, China [4]Department of Neurology, The General Hospital of Chinese People’s Liberation Army, 100853 Beijing, China [5]Department of Neurology, Xuan Wu Hospital of Capital Medical University, 100053 Beijing, China

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Studies on myotonic dystrophy type 1 (DM1) have led to the RNA-mediated disease model for hereditary disorders caused by noncoding 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 (CUGexp) 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 HSALR 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 CUGexp RNA triggers abnormal expression of multiple nuclear RNA binding proteins, including CELF1 and HNRNPA1, that antagonize MBNL activity to promote fetal splicing patterns. Copyright © 2020 the Author(s). Published by PNAS.

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出版当年[2019]版：

大类 | 1 区

综合性期刊

小类 | 1 区综合性期刊

最新[2023]版：

大类 | 1 区

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小类 | 1 区综合性期刊

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出版当年[2018]版：

Q1 MULTIDISCIPLINARY SCIENCES

最新[2023]版：

Q1 MULTIDISCIPLINARY SCIENCES

影响因子： 9.4 最新[2023版] 10.8 最新五年平均 9.58 出版当年[2018版] 10.6 出版当年五年平均 9.504 出版前一年[2017版] 9.412 出版后一年[2019版]

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第一作者机构： [1]School of Life Science and Technology, The Key Laboratory of Developmental Genes and Human Disease, Southeast University, 210096 Nanjing, China [2]Department of Molecular Genetics and Microbiology, Genetics Institute and the Center for NeuroGenetics, University of Florida, College of Medicine, Gainesville, FL 32610 [3]Jiangsu Co-innovation Center of Neuroregeneration, Nantong University, 226001 Nantong, China

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通讯机构： [1]School of Life Science and Technology, The Key Laboratory of Developmental Genes and Human Disease, Southeast University, 210096 Nanjing, China [2]Department of Molecular Genetics and Microbiology, Genetics Institute and the Center for NeuroGenetics, University of Florida, College of Medicine, Gainesville, FL 32610 [3]Jiangsu Co-innovation Center of Neuroregeneration, Nantong University, 226001 Nantong, China

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