Division of Cardiovascular Medicine, Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305.
Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine.
Nature. 2014 Oct 2;514(7520):102-106. doi: 10.1038/nature13596. Epub 2014 Aug 10.
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.
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。据估计，70%的小鼠基因都经历反义转录，包括肌球蛋白重链 7（Myh7），它编码心脏收缩的分子马达蛋白。在这里，我们鉴定了来自 Myh7 基因座的 lncRNA 转录本簇，并证明了一种新的 lncRNA-染色质机制与心力衰竭有关。在小鼠中，这些转录本，我们称之为肌球蛋白重链相关 RNA 转录本（Myheart，或 Mhrt），是心脏特异性的，在成年心脏中丰富表达。病理应激激活 Brg1-Hdac-Parp 染色质抑制复合物，从而抑制心脏中的 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 恢复到应激前水平可保护心脏免受肥大和衰竭的影响。Mhrt 拮抗 Brg1 的功能，Brg1 是一种染色质重塑因子，在应激下被激活，触发异常基因表达和心肌病。Mhrt 阻止 Brg1 识别其基因组 DNA 靶标，从而抑制 Brg1 对染色质的靶向和基因调控。它通过与 Brg1 的解旋酶结构域结合来实现这一点，该结构域对于将 Brg1 与染色质化 DNA 靶标连接至关重要。Brg1 解旋酶具有双重核酸结合特异性：它能够结合 lncRNA（Mhrt）和染色质化但非裸露的 DNA。这种解旋酶的双重结合特性使 Mhrt 能够通过竞争性抑制机制将 Brg1 从其基因组 DNA 靶标中隔离出来，从而阻止染色质重塑。因此，Mhrt-Brg1 反馈回路对于心脏功能至关重要。人 MHRT 也起源于 MYH7 基因座，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。我们的研究鉴定了一种心脏保护性 lncRNA，定义了一种用于 ATP 依赖性染色质重塑因子的新靶向机制，并为 lncRNA-染色质相互作用建立了新的范例。
