A long noncoding RNA protects the heart from pathological hypertrophy

The role oflong noncodingRNA (lncRNA)in adult heartsis unknown; also unclearis how lncRNA modulates nucleosome remodelling. An estimated 70% of mouse genes undergo antisense transcription1 , including myosin heavy chain 7 (Myh7), which encodes molecularmotor proteins for heart contraction2 . 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 abundantin adult hearts. Pathological stress activates the Brg1–Hdac–Parp chromatin repressor complex3 toinhibitMhrttranscriptionin the heart. Such stress-inducedMhrtrepression is essential for cardiomyopathy to develop: restoringMhrtto the prestress 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 myopathy3 . 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 thatis 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 inhibitionmechanism bywhichMhrtsequestersBrg1 fromitsgenomicDNA 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 mechanismin human cardiomyopathy. Our studies identify a cardioprotective lncRNA, define a new targeting mechanism for ATP-dependent chromatinremodelling factors, and establish a new paradigm for lncRNA– chromatin interaction.