title: A long noncoding RNA protects the heart from pathological hypertrophy.
abstract: The role of long noncoding RNA (lncRNA) in adult hearts is unknown; also unclear is how lncRNA modulates nucleosome remodelling. An estimated 70% of mouse genes undergo antisense transcription, including myosin heavy chain 7 (Myh7), which encodes molecular motor proteins for heart contraction. Here we identify a cluster of lncRNA transcripts from Myh7 loci and demonstrate a new lncRNA-chromatin mechanism for heart failure. In mice, these transcripts, which we named myosin heavy-chain-associated RNA transcripts (Myheart, or Mhrt), are cardiac-specific and abundant in adult hearts. Pathological stress activates the Brg1-Hdac-Parp chromatin repressor complex to inhibit Mhrt transcription in the heart. Such stress-induced Mhrt repression is essential for cardiomyopathy to develop: restoring Mhrt to the pre-stress level protects the heart from hypertrophy and failure. Mhrt antagonizes the function of Brg1, a chromatin-remodelling factor that is activated by stress to trigger aberrant gene expression and cardiac myopathy. Mhrt prevents Brg1 from recognizing its genomic DNA targets, thus inhibiting chromatin targeting and gene regulation by Brg1. It does so by binding to the helicase domain of Brg1, a domain that is crucial for tethering Brg1 to chromatinized DNA targets. Brg1 helicase has dual nucleic-acid-binding specificities: it is capable of binding lncRNA (Mhrt) and chromatinized--but not naked--DNA. This dual-binding feature of helicase enables a competitive inhibition mechanism by which Mhrt sequesters Brg1 from its genomic DNA targets to prevent chromatin remodelling. A Mhrt-Brg1 feedback circuit is thus crucial for heart function. Human MHRT also originates from MYH7 loci and is repressed in various types of myopathic hearts, suggesting a conserved lncRNA mechanism in human cardiomyopathy. Our studies identify a cardioprotective lncRNA, define a new targeting mechanism for ATP-dependent chromatin-remodelling factors, and establish a new paradigm for lncRNA-chromatin interaction.
authors.affiliation: Division of Cardiovascular Medicine, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.|Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine.
authors.forename: Pei
authors.initials: P
authors.lastname: Han
authors.affiliation: Division of Cardiovascular Medicine, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Division of Cardiovascular Medicine, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Chiou-Hong
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Division of Cardiovascular Medicine, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.|Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine.
authors.forename: Jin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Division of Cardiovascular Medicine, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Ching
authors.initials: C
authors.lastname: Shang
authors.affiliation: Division of Cardiovascular Medicine, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Sylvia T
authors.initials: ST
authors.lastname: Nuernberg
authors.affiliation: Division of Cardiovascular Medicine, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Kevin Kai
authors.initials: KK
authors.lastname: Jin
authors.affiliation: Stanford Genome Technology Center, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Weihong
authors.initials: W
authors.lastname: Xu
authors.affiliation: Division of Cardiovascular Medicine, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Chieh-Yu
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Division of Cardiovascular Medicine, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Chien-Jung
authors.initials: CJ
authors.lastname: Lin
authors.affiliation: Division of Cardiovascular Medicine, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Yiqin
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Division of Cardiovascular Medicine, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Huanchieh
authors.initials: H
authors.lastname: Chien
authors.affiliation: Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine of Yeshiva University, 1301 Morris Park Avenue, Price Center 420, Bronx, NY 10461.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Division of Cardiovascular Medicine, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Euan
authors.initials: E
authors.lastname: Ashley
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bernstein
authors.affiliation: Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine.
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
authors.affiliation: Del E. Webb Neuroscience, Aging & Stem Cell Research Center, Sanford/Burnham Medical Research Institute, La Jolla, California 92037.
authors.forename: Huei-Sheng Vincent
authors.initials: HV
authors.lastname: Chen
authors.affiliation: Division of Cardiovascular Medicine, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
authors.affiliation: Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine.|Department of Biochemistry and Molecular Biology.|Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Ching-Pin
authors.initials: CP
authors.lastname: Chang
mesh_terms: D000818:Animals; D024722:Cardiac Myosins / Q000235:genetics; D006332:Cardiomegaly / Q000235:genetics* / Q000473:pathology* / Q000517:prevention & control; D009202:Cardiomyopathies / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D004265:DNA Helicases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D006333:Heart Failure / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051379:Mice; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D062085:RNA, Long Noncoding / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D002843:Chromatin; C501641:MYH7 protein, human; C551613:Myh7 protein, mouse; D009687:Nuclear Proteins; D062085:RNA, Long Noncoding; D014157:Transcription Factors; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D006655:Histone Deacetylases; D024722:Cardiac Myosins; C513194:Smarca4 protein, mouse; D004265:DNA Helicases; D018995:Myosin Heavy Chains