Novel Mechanisms of LncRNA Mediated Epigenetic Regulation in Cardiac Hypertrophy

摘要 转录组重编程是心脏肥大和病理性重塑的核心。最近 基因组学的进步极大地扩展了心脏转录组的范围和功能， 远远超出了编码基因，包括许多非编码基因。特别是，大量的长非编码 RNA（所谓的lncRNA）已在心脏转录组中被鉴定，然而，它们的大部分功能仍然存在。 未开发的在导致这一提议的初步研究中，我们发现了一种新的心脏富集lncRNA， 在小鼠、大鼠和人心脏中表达，其被证明对压力过载诱导的 心脏肥大此外，我们证明这种lncRNA与染色质特异性相互作用 修饰复合物PRC 2以调节应激心脏中病理基因上的H3 K27 me 2/3水平，因此我们 将这种lncRNA命名为心脏肥大相关表观遗传调节因子（Chaer）。最有趣的是，我们 发现Chaer在mTOR中肥大刺激开始时与PRC 2瞬时相互作用 依赖的方式。这种短暂的相互作用似乎对早期发作很重要，但对随后的 心脏肥大和心力衰竭的进展。因此，Chaer-PRC 2相互作用似乎是一种 心脏肥大基因表达和重塑所必需的早期表观遗传检查点。这 这一发现强调了lncRNA在转录调控中的两个潜在的非常重要的作用：一个是作为一个 分子开关连接表观遗传修饰剂与细胞应激信号，另一个作为分子伴侣 在特定组织的背景下为普遍存在的表观遗传修饰物协调靶特异性。进一步 建立这一新的概念，我们建议大力研究Chaer介导的心脏 通过实现以下三个具体目标进行基因调控：目标1。为了揭示 肥大信号调节Chaer和PRC 2之间的相互作用。目标2.为了调查查尔 相互作用调节Ezh 2功能响应肥大刺激。目标3：建立 Chaer-PRC 2相互作用对心脏表观遗传调节和转录组的功能影响 心脏肥大时的重编程实现这些目标将填补我们目前的一个重大空白。 对心肌肥厚表观遗传调控认识， 心脏细胞中可诱导的基因座特异性染色质修饰。

Abstract Transcriptome reprogramming is central to cardiac hypertrophy and pathological remodeling. Recent advances in genomics have dramatically expanded the scope and function of the cardiac transcriptome to cover much beyond the coding genes to include many non-coding genes. In particular, a vast cohort of long non-coding RNAs (so called lncRNAs) have been identified in cardiac transcriptome, yet, much of their functions remain unexplored. In preliminary studies leading to this proposal, we discovered a novel cardiac-enriched lncRNA expressed in mouse, rat and human heart which is demonstrated to be essential to pressure overload-induced cardiac hypertrophy. Furthermore, we demonstrated that this lncRNA interacts specifically with the chromatin modifying complex PRC2 to modulate H3K27me2/3 levels on pathological genes in stressed heart, thus we named this lncRNA as Cardiac Hypertrophy Associated Epigenetic Regulator (Chaer). Most intriguingly, we found Chaer transiently interacts with PRC2 transient at the onset of hypertrophic stimulation in an mTOR dependent manner. This transient interaction appears to be important to the early onset but not the subsequent progression of cardiac hypertrophy and heart failure. Therefore, the Chaer-PRC2 interaction appears to be an early epigenetic check-point necessary for hypertrophic gene expression and remodeling in the heart. This discovery highlights two potentially very important roles for lncRNAs in transcription regulation: one as a molecular switch to link epigenetic modifiers with cellular stress signals, and another as a molecular chaperon to orchestrate target specificity in the context of specific tissues for ubiquitous epigenetic modifiers. To further establish this novel concept, we propose to vigorously investigate the mechanism of Chaer mediated cardiac gene regulation by achieving the following three specific aims: Aim 1. To uncover the molecular basis for hypertrophic signal regulated interaction between Chaer and PRC2. Aim 2. To investigate how Chaer interaction regulates Ezh2 function in response to hypertrophic stimulation. Aim 3. To establish the functional impact of Chaer-PRC2 interaction on cardiac epigenetic modulation and transcriptome reprogramming during cardiac hypertrophy. Accomplishing these aims will fill a major gap in our current knowledge of epigenetic regulation in cardiac hypertrophy and advance our mechanistic understanding of inducible, locus-specific chromatin modification in heart cells.