@article{443370fb99314bd9a767f8c35d4f9b0d,
title = "The lncRNA H19 alleviates muscular dystrophy by stabilizing dystrophin",
abstract = "Dystrophin proteomic regulation in muscular dystrophies (MDs) remains unclear. We report that a long noncoding RNA (lncRNA), H19, associates with dystrophin and inhibits E3-ligase-dependent polyubiquitination at Lys 3584 (referred to as Ub-DMD) and its subsequent protein degradation. In-frame deletions in BMD and a DMD non-silent mutation (C3340Y) resulted in defects in the ability of the protein to interact with H19, which caused elevated Ub-DMD levels and dystrophin degradation. Dmd C3333Y mice exhibited progressive MD, elevated serum creatine kinase, heart dilation, blood vessel irregularity and respiratory failure with concurrently reduced dystrophin and increased Ub-DMD status. H19 RNA oligonucleotides conjugated with agrin (AGR–H19) and nifenazone competed with or inhibited TRIM63. Dmd C3333Y animals, induced-pluripotent-stem-cell-derived skeletal muscle cells from patients with Becker MD and mdx mice subjected to exon skipping exhibited inhibited dystrophin degradation, preserved skeletal and cardiac muscle histology, and improved strength and heart function following AGR–H19 or nifenazone treatment. Our study paves the way for meaningful targeted therapeutics for Becker MD and for certain patients with Duchenne MD.",
author = "Yaohua Zhang and Yajuan Li and Qingsong Hu and Yutao Xi and Zhen Xing and Zhao Zhang and Lisa Huang and Jianbo Wu and Ke Liang and Nguyen, {Tina K.} and Egranov, {Sergey D.} and Chengcao Sun and Zilong Zhao and Hawke, {David H.} and Jin Li and Deqiang Sun and Kim, {Jean J.} and Ping Zhang and Jie Cheng and Abid Farida and Hung, {Mien Chie} and Leng Han and Radbod Darabi and Chunru Lin and Liuqing Yang",
note = "Funding Information: We would like to thank the Baylor College of Medicine Human Stem Cell Core (HSCC) for technical help and consultation for iPSC line derivation, maintenance and differentiation. The HSCC is supported in part by Shared Resource funding from the NIH (CA125123, PI: Osborne). The generation of knock-in mice was supported by CCSG grant NCI number CA016672 (GEMF) of the MD Anderson Cancer Center. The Proteomics and Metabolomics Facility was supported in part by Cancer Prevention Research Institute of Texas (CPRIT) grant number RP130397 and NIH grant numbers 1S10OD012304-01 and P30CA016672. This work was partially supported by the Texas A&M University Chancellor{\textquoteright}s Research Initiative. This work was partially supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the NIH under award numbers 1R01AR068293 and 1R21AR071583 to R.D. This work was partially supported by the Cancer Prevention and Research Institute of Texas (RR150085) and CPRIT Scholar in Cancer Research (to L. Han). This work was supported by NIH R01 awards (1 R01 CA218025-01, 1R01CA231011-01), a CPRIT individual investigator research award (180259) and a DoD Breakthrough award (BC180196) to C.L., and a NIH R01 award (1 R01 CA218036-01) and DoD Breakthrough awards (BC151465, BC181384), a CPRIT individual investigator research award (200423) and a Andrew Sabin Family Foundation Fellows award to L.Y. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2020",
month = nov,
day = "1",
doi = "10.1038/s41556-020-00595-5",
language = "English (US)",
volume = "22",
pages = "1332--1345",
journal = "Nature cell biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "11",
}