A long noncoding RNA protects the heart from pathological hypertrophy

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

Research output: Contribution to journalArticle

288 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)102-106
Number of pages5
JournalNature
Volume514
Issue number7520
DOIs
StatePublished - Oct 2 2014

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Long Noncoding RNA
Cardiomegaly
Chromatin
Chromatin Assembly and Disassembly
Myosin Heavy Chains
DNA
Cardiomyopathies
Heart Failure
Molecular Motor Proteins
Gene Targeting
Nucleosomes
Muscular Diseases
Nucleic Acids
Adenosine Triphosphate
RNA
Gene Expression

ASJC Scopus subject areas

  • General

Cite this

Han, P., Li, W., Lin, C. H., Yang, J., Shang, C., Nurnberg, S. T., ... Chang, C-P. (2014). A long noncoding RNA protects the heart from pathological hypertrophy. Nature, 514(7520), 102-106. https://doi.org/10.1038/nature13596

A long noncoding RNA protects the heart from pathological hypertrophy. / Han, Pei; Li, Wei; Lin, Chiou Hong; Yang, Jin; Shang, Ching; Nurnberg, Sylvia T.; Jin, Kevin Kai; Xu, Weihong; Lin, Chieh Yu; Lin, Chien Jung; Xiong, Yiqin; Chien, Huan Chieh; Zhou, Bin; Ashley, Euan; Bernstein, Daniel; Chen, Peng-Sheng; Chen, Huei Sheng Vincent; Quertermous, Thomas; Chang, Ching-Pin.

In: Nature, Vol. 514, No. 7520, 02.10.2014, p. 102-106.

Research output: Contribution to journalArticle

Han, P, Li, W, Lin, CH, Yang, J, Shang, C, Nurnberg, ST, Jin, KK, Xu, W, Lin, CY, Lin, CJ, Xiong, Y, Chien, HC, Zhou, B, Ashley, E, Bernstein, D, Chen, P-S, Chen, HSV, Quertermous, T & Chang, C-P 2014, 'A long noncoding RNA protects the heart from pathological hypertrophy', Nature, vol. 514, no. 7520, pp. 102-106. https://doi.org/10.1038/nature13596
Han P, Li W, Lin CH, Yang J, Shang C, Nurnberg ST et al. A long noncoding RNA protects the heart from pathological hypertrophy. Nature. 2014 Oct 2;514(7520):102-106. https://doi.org/10.1038/nature13596
Han, Pei ; Li, Wei ; Lin, Chiou Hong ; Yang, Jin ; Shang, Ching ; Nurnberg, Sylvia T. ; Jin, Kevin Kai ; Xu, Weihong ; Lin, Chieh Yu ; Lin, Chien Jung ; Xiong, Yiqin ; Chien, Huan Chieh ; Zhou, Bin ; Ashley, Euan ; Bernstein, Daniel ; Chen, Peng-Sheng ; Chen, Huei Sheng Vincent ; Quertermous, Thomas ; Chang, Ching-Pin. / A long noncoding RNA protects the heart from pathological hypertrophy. In: Nature. 2014 ; Vol. 514, No. 7520. pp. 102-106.
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