Regulation of cardiac hypertrophy and failure by the histone methyltransferase Smyd1

 描述(由申请人提供)：心肌肥大是心力衰竭的常见先兆，是对以心肌细胞生长为特征的工作量增加的代偿性反应。肥大的心肌细胞通过采用胎儿心肌细胞的表达谱和一些表型特征，经历了细胞可塑性的显著变化。这一现象代表了驱动心脏病形态和生理重塑的分子基础，可能包括旨在减轻疾病诱导的重塑的适应不良和代偿机制。为了实现基因表达的这些变化，染色质结构必须经历显著的变化，以沉默或激活基因组的特定区域。最近在小鼠心肌肥厚模型上的研究表明，调节关键的表观遗传因子可以抑制这些基因的表达变化，防止病理重塑；然而，我们对染色质修饰物驱动心脏疾病的了解相当有限。Smyd1是一种肌细胞特异性的组蛋白甲基转移酶，最初被认为是结构性Smyd1基因敲除小鼠心脏发育的必要调节因子，这些小鼠因心脏缺陷而在子宫中死亡。最近，我们发现Smyd1的表达在小鼠压力超负荷肥大和衰竭期间受到差异调控(与其在人类中的表达一致)，并控制成人心脏的病理基因表达和心肌细胞的生长。最耐人寻味的是，来自分离的心肌细胞的数据表明，Smyd1a变体的过度表达可以抑制疾病诱导的重构，这表明这一途径可能具有治疗靶向的前景。尽管有这些发现，但对Smyd1‘S在成人心肌中的分子功能知之甚少。这项应用将利用独特的遗传动物模型和最先进的蛋白质组学和下一代测序技术，从概念上促进我们对心力衰竭的理解。具体地说，这项工作将确定Smyd1a是否可以抑制肥厚和衰竭动物模型的生长和病理重塑，并确定影响Smyd1的S活性、基因组靶向和功能变异的因素。此外，这项工作将通过确定Smyd1变体结合的基因来最终确定Smyd1如何调节心肌中的生长，并研究结合如何影响转录。这种方法将揭示控制病理生长的离散分子机制，而且它有可能为组蛋白甲基转移酶如何调节染色质结构从而调节心脏表型提供改变范式的见解。最终，表征这一新的、心肌细胞特异性信号通路的组成部分可能会揭示心力衰竭的新治疗靶点。

 DESCRIPTION (provided by applicant): Cardiac hypertrophy, a common precursor to heart failure, is a compensatory response to an increased workload characterized by myocyte growth. Hypertrophic cardiomyocytes undergo significant changes in cellular plasticity by adopting the expression profile and some phenotypic aspects of fetal cardiac cells. This phenomenon represents the molecular underpinnings driving the morphological and physiological remodeling in heart disease and likely includes both maladaptive and compensatory mechanisms aimed at mitigating disease-induced remodeling. To execute these changes in gene expression, chromatin structure must undergo significant alterations to silence or activate select regions of the genome. Recent studies in murine models of cardiac hypertrophy have demonstrated that modulating key epigenetic factors can inhibit these gene expression changes and prevent pathologic remodeling; however, our knowledge of the chromatin modifiers driving cardiac disease is quite limited. Smyd1, a myocyte-specific histone methyltransferase, was originally identified as a necessary regulator of cardiac development in constitutive Smyd1 knockout mice, which die in utero due to cardiac defects. More recently, we have shown that Smyd1 expression is differentially regulated during pressure overload hypertrophy and failure in mice (consistent with its expression in humans) and that it controls pathologic gene expression and myocyte growth in the adult heart. Most intriguing, data from isolated myocytes show that over-expression of the Smyd1a variant can inhibit disease induced remodeling, suggesting this pathway may hold promise for therapeutic targeting. Despite these findings, very little is known regarding Smyd1's molecular function in the adult myocardium. This application will leverage a unique genetic animal model and state-of-the-art proteomic and next- generation sequencing technologies to conceptually advance our understanding of heart failure. Specifically, this work will determine if Smyd1a can inhibit growth and pathologic remodeling in an animal model of hypertrophy and failure and identify the factors governing Smyd1's activity, genomic targeting and functional variance. In addition this work will conclusively determine how Smyd1 regulates growth in the myocardium by identifying the genes bound by Smyd1 variants, and investigate how binding affects transcription. This approach will reveal discrete molecular mechanisms governing pathologic growth, but moreover, it has the potential to provide paradigm changing insights into how histone methyltransferases regulate chromatin structure and thereby cardiac phenotype. Ultimately, characterizing the components of this novel, myocyte-specific signaling pathway could reveal new therapeutic targets for heart failure.