A long noncoding RNA protects the heart from pathological hypertrophy.
A long noncoding RNA protects the heart from pathological hypertrophy.
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DOI：
10.1038/nature13596
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发表时间：
2014-10-02
期刊：
影响因子：
64.8
通讯作者：
Chang, Ching-Pin
中科院分区：
文献类型：
--
作者：
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
长链非编码RNA（lncRNA）在成人心脏中的作用尚不清楚; lncRNA如何调节核小体重塑也不清楚。估计70%的小鼠基因经历反义转录，包括编码心脏收缩的分子马达蛋白的肌球蛋白重链7（Myh 7）。在这里，我们确定了一个集群的lncRNA转录Myh 7基因座，并显示了一个新的lncRNA染色质的机制，心力衰竭。在小鼠中，这些转录物，我们命名为肌球蛋白重链相关RNA转录物（MyHEART或Mhrt），是心脏特异性的，在成年心脏中丰富。病理性应激激活Brg 1-Hdac-Parp染色质阻遏物复合物以抑制心脏中的Mhrt转录。这种应激诱导的Mhrt抑制对于心肌病的发展是必不可少的：将Mhrt恢复到应激前的水平可以保护心脏免于肥大和衰竭。Mhrt拮抗Brg 1的功能，Brg 1是一种染色质重塑因子，在应激时被激活以触发异常基因表达和心肌病。Mhrt阻止Brg 1识别其基因组DNA靶标，从而抑制Brg 1的染色质靶向和基因调控。Mhrt与Brg 1的解旋酶结构域结合，该结构域对于将Brg 1连接到染色质化的DNA靶标至关重要。Brg 1解旋酶具有双重核酸结合特异性：它能够结合lncRNA（Mhrt）和染色质化DNA，但不能结合裸DNA。解旋酶的这种双重结合特征使得Mhrt能够通过竞争性抑制机制将Brg 1与其基因组DNA靶点隔离以防止染色质重塑。因此，Mhrt-Brg 1反馈电路对心脏功能至关重要。人类MHRT也起源于MYH 7基因座，并在各种类型的肌病心脏中受到抑制，这表明人类心肌病中存在保守的lncRNA机制。我们的研究确定了第一个心脏保护性lncRNA，定义了一个新的ATP依赖性染色质重塑因子的靶向机制，并建立了一个新的lncRNA-染色质相互作用的范例。
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, including myosin heavy chain 7 (Myh7) that encodes molecular motor proteins for heart contraction. 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 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. 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.
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影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
DOI：
10.1093/bioinformatics/btr209
发表时间：
2011-07-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Lin MF;Jungreis I;Kellis M
通讯作者：
Kellis M
影响因子：
64.8
作者：
Mallam, Anna L.;Del Campo, Mark;Gilman, Benjamin;Sidote, David J.;Lambowitz, Alan M.
通讯作者：
Lambowitz, Alan M.
影响因子：
64.5
作者：
Liu, R;Liu, H;Zhao, KJ
通讯作者：
Zhao, KJ
影响因子：
64.5
作者：
Chang, CP;Neilson, JR;Crabtree, GR
通讯作者：
Crabtree, GR