Regulation of cardiac hypertrophy and failure by the histone methyltransferase Smyd1

组蛋白甲基转移酶 Smyd1 对心脏肥大和衰竭的调节

• 批准号: 9198054
• 负责人: Sarah Franklin
• 金额: $ 37.25万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198054
• 关键词: Adopted; Adult; Affect; Animal Genetics; Animal Model; Automobile Driving; Award; Binding; Biological Assay; Cardiac; Cardiac Myocytes; Cardiac development; Cause of Death; Cells; ChIP-seq; Chromatin; Chromatin Structure; Complex; Data; Disease; Epigenetic Process; Failure; Funding; Gene Expression; Genes; Genetic Models; Genetic Transcription; Genome; Genomics; Growth; Heart; Heart Abnormalities; Heart Diseases; Heart Hypertrophy; Heart failure; Histones; Homeostasis; Human; Hypertrophy; Knockout Mice; Knowledge; Luciferases; Mass Spectrum Analysis; Methodology; Modification; Molecular; Molecular Profiling; Morphology; Mus; Muscle Cells; Myocardium; Nucleosomes; Participant; Pathologic; Pathology; Pathway interactions; Phenotype; Phenylephrine; Physiological; Post-Translational Protein Processing; Proteins; Proteomics; Publications; Regulation; Reporter; Role; Signal Pathway; Signal Transduction; Stimulus; Technology; Testing; Therapeutic; Transcription Repressor/Corepressor; Transcriptional Activation; United States; Variant; Work; Workload; cell growth; chromatin immunoprecipitation; combat; experimental study; fetal; gene repression; genetic regulatory protein; histone methyltransferase; in utero; in vivo; insight; mouse model; new therapeutic target; next generation sequencing; novel; overexpression; pressure; prevent; promoter; public health relevance; response; therapeutic target

 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.

 描述（由适用提供）：心脏衰竭的常见前体是对肌细胞生长增加工作量表征的补偿性反应。通过采用表达谱和胎儿心脏细胞的某些表型方面，肥厚的心肌细胞会在细胞可塑性上发生显着变化。这种现象代表了驱动心脏疾病形态和物理重塑的分子基础，并且可能包括适应性和补偿机制，旨在减轻疾病引起的重塑。为了在基因表达中执行这些变化，染色质结构必须经历重大变化，以使基因组的精选区域保持沉默或激活。在心脏肥大的鼠模型中的最新研究表明，调节关键的表观遗传因子可以抑制这些基因表达的变化并防止病理重塑。但是，我们对驱动心脏病的染色质修饰剂的了解非常有限。 SMYD1是一种肌细胞特异性组蛋白甲基转移酶，最初被确定为组成型SMYD1敲除小鼠心脏发育的必要调节剂，由于心脏缺陷而在子宫内死亡。最近，我们已经表明，在压力超负荷肥大和小鼠的失败期间，SMYD1表达受到差异调节（与其在人类中的表达一致），并且它控制了成人心脏中的病理基因表达和心肌细胞的生长。来自分离的肌细胞的最吸引人的数据表明，SMYD1A变体的过表达可以抑制疾病诱导的重塑，这表明该途径可能对治疗靶向有希望。尽管有这些发现，但对于成年心肌中SMYD1的分子功能知之甚少。该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来概念上提高我们对心力衰竭的理解。具体而言，这项工作将确定SMYD1A是否可以抑制肥大和失败模型中的生长和病理重塑，并确定有关SMYD1活性，基因组靶向和功能差异的因素。此外，这项工作将最终确定SMYD1如何通过鉴定由SMYD1变体结合的基因来调节心肌的生长，并研究结合如何影响转录。这种方法将揭示有关病理生长的离散分子机制，但此外，它有可能提供范式改变组蛋白甲基转移酶如何调节染色质结构并从而提供心脏表型的范式。最终，描述了这种小说的组成部分，肌细胞特异性信号通路可以揭示出新的心力衰竭治疗靶标。