Jinjing Zhao1, Wei Zhang1, Mingyan Lin1, Wen Wu1, Pengtao Jiang1, Emiley Tou1, Min Xue1, Angelene Richards1, David Jourd'heuil1, Arif Asif1, Deyou Zheng1, Harold A Singer1, Joseph M Miano1, Xiaochun Long2. 1. From the Department of Molecular and Cellular Physiology (J.Z., W.Z., W.W., E.T., M.X., A.R., D.J., H.A.S., X.L.), Albany Medical College, NY; Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ (A.A.); Departments of Genetics (M.L., D.Z.) and Neurology and Neuroscience (D.Z.), Albert Einstein College of Medicine, Bronx, NY; Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, NY (P.J., J.M.M.); and National Aquafeed Safety Assessment Center, Feed Research Institute, Chinese Academy of Agricultural Sciences, Beijing, P.R. China (M.X.). 2. From the Department of Molecular and Cellular Physiology (J.Z., W.Z., W.W., E.T., M.X., A.R., D.J., H.A.S., X.L.), Albany Medical College, NY; Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ (A.A.); Departments of Genetics (M.L., D.Z.) and Neurology and Neuroscience (D.Z.), Albert Einstein College of Medicine, Bronx, NY; Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, NY (P.J., J.M.M.); and National Aquafeed Safety Assessment Center, Feed Research Institute, Chinese Academy of Agricultural Sciences, Beijing, P.R. China (M.X.). longx@mail.amc.edu.
Abstract
OBJECTIVE: Long noncoding RNAs (lncRNA) represent a growing class of noncoding genes with diverse cellular functions. We previously reported on SENCR, an lncRNA that seems to support the vascular smooth muscle cell (VSMC) contractile phenotype. However, information about the VSMC-specific lncRNAs regulated by myocardin (MYOCD)/serum response factor, the master switch for VSMC differentiation, is unknown. APPROACH AND RESULTS: To define novel lncRNAs with functions related to VSMC differentiation, we performed RNA sequencing in human coronary artery SMCs that overexpress MYOCD. Several novel lncRNAs showed altered expression with MYOCD overexpression and one, named MYOcardin-induced Smooth muscle LncRNA, Inducer of Differentiation (MYOSLID), was activated by MYOCD and selectively expressed in VSMCs. MYOSLID was a direct transcriptional target of both MYOCD/serum response factor and transforming growth factor-β/SMAD pathways. Functional studies revealed that MYOSLID promotes VSMC differentiation and inhibits VSMC proliferation. MYOSLID showed reduced expression in failed human arteriovenous fistula samples compared with healthy veins. Although MYOSLID did not affect gene expression of transcription factors, such as serum response factor and MYOCD, its depletion in VSMCs disrupted actin stress fiber formation and blocked nuclear translocation of MYOCD-related transcription factor A (MKL1). Finally, loss of MYOSLID abrogated transforming growth factor-β1-induced SMAD2 phosphorylation. CONCLUSIONS: We have demonstrated that MYOSLID, the first human VSMC-selective and serum response factor/CArG-dependent lncRNA, is a novel modulator in amplifying the VSMC differentiation program, likely through feed-forward actions of both MKL1 and transforming growth factor-β/SMAD pathways.
OBJECTIVE: Long noncoding RNAs (lncRNA) represent a growing class of noncoding genes with diverse cellular functions. We previously reported on SENCR, an lncRNA that seems to support the vascular smooth muscle cell (VSMC) contractile phenotype. However, information about the VSMC-specific lncRNAs regulated by myocardin (MYOCD)/serum response factor, the master switch for VSMC differentiation, is unknown. APPROACH AND RESULTS: To define novel lncRNAs with functions related to VSMC differentiation, we performed RNA sequencing in human coronary artery SMCs that overexpress MYOCD. Several novel lncRNAs showed altered expression with MYOCD overexpression and one, named MYOcardin-induced Smooth muscle LncRNA, Inducer of Differentiation (MYOSLID), was activated by MYOCD and selectively expressed in VSMCs. MYOSLID was a direct transcriptional target of both MYOCD/serum response factor and transforming growth factor-β/SMAD pathways. Functional studies revealed that MYOSLID promotes VSMC differentiation and inhibits VSMC proliferation. MYOSLID showed reduced expression in failed humanarteriovenous fistula samples compared with healthy veins. Although MYOSLID did not affect gene expression of transcription factors, such as serum response factor and MYOCD, its depletion in VSMCs disrupted actin stress fiber formation and blocked nuclear translocation of MYOCD-related transcription factor A (MKL1). Finally, loss of MYOSLID abrogated transforming growth factor-β1-induced SMAD2 phosphorylation. CONCLUSIONS: We have demonstrated that MYOSLID, the first humanVSMC-selective and serum response factor/CArG-dependent lncRNA, is a novel modulator in amplifying the VSMC differentiation program, likely through feed-forward actions of both MKL1 and transforming growth factor-β/SMAD pathways.
Authors: Xiaochun Long; Darla L Tharp; Mary A Georger; Orazio J Slivano; Monica Y Lee; Brian R Wamhoff; Douglas K Bowles; Joseph M Miano Journal: J Biol Chem Date: 2009-10-01 Impact factor: 5.157
Authors: Nianwei Lin; Kung-Yen Chang; Zhonghan Li; Keith Gates; Zacharia A Rana; Jason Dang; Danhua Zhang; Tianxu Han; Chao-Shun Yang; Thomas J Cunningham; Steven R Head; Gregg Duester; P Duc Si Dong; Tariq M Rana Journal: Mol Cell Date: 2014-02-13 Impact factor: 17.970
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311