Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
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
_version_ 1782337942119776256
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
work_keys_str_mv AT hanpei alongnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT liwei alongnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT linchiouhong alongnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT yangjin alongnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT shangching alongnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT nuernbergsylviat alongnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT jinkevinkai alongnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT xuweihong alongnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT linchiehyu alongnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT linchienjung alongnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT xiongyiqin alongnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT chienhuanchieh alongnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT zhoubin alongnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT ashleyeuan alongnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT bernsteindaniel alongnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT chenpengsheng alongnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT chenhueishengvincent alongnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT quertermousthomas alongnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT changchingpin alongnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT hanpei longnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT liwei longnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT linchiouhong longnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT yangjin longnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT shangching longnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT nuernbergsylviat longnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT jinkevinkai longnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT xuweihong longnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT linchiehyu longnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT linchienjung longnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT xiongyiqin longnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT chienhuanchieh longnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT zhoubin longnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT ashleyeuan longnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT bernsteindaniel longnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT chenpengsheng longnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT chenhueishengvincent longnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT quertermousthomas longnoncodingrnaprotectstheheartfrompathologicalhypertrophy
AT changchingpin longnoncodingrnaprotectstheheartfrompathologicalhypertrophy