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A long non-coding RNA protects the heart from pathological hypertrophy
The role of long noncoding RNA (lncRNA) in adult hearts is unknown; also unclear is how lncRNA modulates nucleosome remodeling. An estimated 70% of mouse genes undergo antisense transcription(1), including myosin heavy chain 7 (Myh7) that encodes molecular motor proteins for heart contraction(2). He...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184960/ https://www.ncbi.nlm.nih.gov/pubmed/25119045 http://dx.doi.org/10.1038/nature13596 |
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author | Han, Pei Li, Wei Lin, Chiou-Hong Yang, Jin Shang, Ching Nuernberg, Sylvia T. Jin, Kevin Kai Xu, Weihong Lin, Chieh-Yu Lin, Chien-Jung Xiong, Yiqin Chien, Huanchieh Zhou, Bin Ashley, Euan Bernstein, Daniel Chen, Peng-Sheng Chen, Huei-sheng Vincent Quertermous, Thomas Chang, Ching-Pin |
author_facet | Han, Pei Li, Wei Lin, Chiou-Hong Yang, Jin Shang, Ching Nuernberg, Sylvia T. Jin, Kevin Kai Xu, Weihong Lin, Chieh-Yu Lin, Chien-Jung Xiong, Yiqin Chien, Huanchieh Zhou, Bin Ashley, Euan Bernstein, Daniel Chen, Peng-Sheng Chen, Huei-sheng Vincent Quertermous, Thomas Chang, Ching-Pin |
author_sort | Han, Pei |
collection | PubMed |
description | The role of long noncoding RNA (lncRNA) in adult hearts is unknown; also unclear is how lncRNA modulates nucleosome remodeling. An estimated 70% of mouse genes undergo antisense transcription(1), including myosin heavy chain 7 (Myh7) that encodes molecular motor proteins for heart contraction(2). Here, we identify a cluster of lncRNA transcripts from Myh7 loci and show 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-remodeling 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. Mhrt binds to the helicase domain of Brg1, and this domain 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 remodeling. 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 the first cardioprotective lncRNA, define a new targeting mechanism for ATP-dependent chromatin-remodeling factors, and establish a new paradigm for lncRNA–chromatin interaction. |
format | Online Article Text |
id | pubmed-4184960 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
record_format | MEDLINE/PubMed |
spelling | pubmed-41849602015-04-02 A long non-coding RNA protects the heart from pathological hypertrophy Han, Pei Li, Wei Lin, Chiou-Hong Yang, Jin Shang, Ching Nuernberg, Sylvia T. Jin, Kevin Kai Xu, Weihong Lin, Chieh-Yu Lin, Chien-Jung Xiong, Yiqin Chien, Huanchieh Zhou, Bin Ashley, Euan Bernstein, Daniel Chen, Peng-Sheng Chen, Huei-sheng Vincent Quertermous, Thomas Chang, Ching-Pin Nature Article The role of long noncoding RNA (lncRNA) in adult hearts is unknown; also unclear is how lncRNA modulates nucleosome remodeling. An estimated 70% of mouse genes undergo antisense transcription(1), including myosin heavy chain 7 (Myh7) that encodes molecular motor proteins for heart contraction(2). Here, we identify a cluster of lncRNA transcripts from Myh7 loci and show 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-remodeling 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. Mhrt binds to the helicase domain of Brg1, and this domain 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 remodeling. 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 the first cardioprotective lncRNA, define a new targeting mechanism for ATP-dependent chromatin-remodeling factors, and establish a new paradigm for lncRNA–chromatin interaction. 2014-08-10 2014-10-02 /pmc/articles/PMC4184960/ /pubmed/25119045 http://dx.doi.org/10.1038/nature13596 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Han, Pei Li, Wei Lin, Chiou-Hong Yang, Jin Shang, Ching Nuernberg, Sylvia T. Jin, Kevin Kai Xu, Weihong Lin, Chieh-Yu Lin, Chien-Jung Xiong, Yiqin Chien, Huanchieh Zhou, Bin Ashley, Euan Bernstein, Daniel Chen, Peng-Sheng Chen, Huei-sheng Vincent Quertermous, Thomas Chang, Ching-Pin A long non-coding RNA protects the heart from pathological hypertrophy |
title | A long non-coding RNA protects the heart from pathological hypertrophy |
title_full | A long non-coding RNA protects the heart from pathological hypertrophy |
title_fullStr | A long non-coding RNA protects the heart from pathological hypertrophy |
title_full_unstemmed | A long non-coding RNA protects the heart from pathological hypertrophy |
title_short | A long non-coding RNA protects the heart from pathological hypertrophy |
title_sort | long non-coding rna protects the heart from pathological hypertrophy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184960/ https://www.ncbi.nlm.nih.gov/pubmed/25119045 http://dx.doi.org/10.1038/nature13596 |
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