Journal Article

A long noncoding RNA protects the heart from pathological hypertrophy

Shang, Ching, Xiong, Yiqin, Zhou, Bin, Nurnberg, Sylvia T., Lin, Chien-Jung, Quertermous, Thomas, Li, Wei, Jin, Kevin Kai, Han, Pei, Chen, Huei-Sheng Vincent, Xu, Weihong, Chien, Huan-Chieh, Lin, Chieh-Yu, Yang, Jin, Chen, Peng-Sheng, Ashley, Euan, Lin, Chiou-Hong, Bernstein, Daniel, Chang, Ching-Pin

2014

Overview

Here, a long noncoding RNA, termed Mhrt , is identified in the loci of myosin heavy chain ( Myh ) genes in mice and shown to be capable of suppressing cardiomyopathy in the animals, as well as being repressed in diseased human hearts. A lncRNA for cardioprotection Ching-Pin Chang and colleagues identify a cardioprotective long noncoding RNA (lncRNA) in the loci of the myosin heavy chain genes Myh6 and Myh7 . The lncRNA, termed Mhrt , is capable of suppressing cardiomyopathy, probably by binding the helicase domain of the chromatin remodelling factor Brg1 and preventing it from recognizing its genomic targets. In turn, Mhrt is negatively regulated by the Brg1–Hdac–Parp1 complex during pathological stress and is repressed in diseased human hearts. Restoring Mhrt expression in the stressed heart protects the heart from hypertrophy and failure. 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 1 , including myosin heavy chain 7 ( Myh7 ), which encodes molecular motor proteins for heart contraction 2 . 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 3 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 3 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 13/109 / 45/15 / 45/91 / 631/208/176 / 631/337/384/2568 / 631/443/592/75 / 64/110 / 64/60 / 82/80 / 82/83 / Animals / Cardiac Myosins - genetics / Cardiomegaly - genetics / Cardiomegaly - pathology / Cardiomegaly - prevention & control / Cardiomyocytes / Cardiomyopathies - genetics / Cardiomyopathies - pathology / Cardiomyopathies - prevention & control / Cardiomyopathy / Chromatin - genetics / Chromatin - metabolism / Chromatin Assembly and Disassembly / Deoxyribonucleic acid / DNA / DNA Helicases - antagonists & inhibitors / DNA Helicases - chemistry / DNA Helicases - genetics / DNA Helicases - metabolism / Feedback, Physiological / Genetic aspects / Heart / Heart Failure - genetics / Heart Failure - pathology / Heart Failure - prevention & control / Histone Deacetylases - metabolism / Humanities and Social Sciences / Humans / Hypertrophy / letter / Mice / multidisciplinary / Myocardium - metabolism / Myocardium - pathology / Myosin Heavy Chains - genetics / Nuclear Proteins - antagonists & inhibitors / Nuclear Proteins - chemistry / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Organ Specificity / Pathology / Physiological aspects / Poly (ADP-Ribose) Polymerase-1 / Poly(ADP-ribose) Polymerases - metabolism / Protein Binding / Protein Structure, Tertiary / Ribonucleic acid / RNA / RNA polymerase / RNA, Long Noncoding - antagonists & inhibitors / RNA, Long Noncoding - genetics / RNA, Long Noncoding - metabolism / Rodents / Science / Transcription Factors - antagonists & inhibitors / Transcription Factors - chemistry / Transcription Factors - genetics / Transcription Factors - metabolism