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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：心脏肥大是心力衰竭的常见前兆，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脏的表达谱和一些表型方面而经历细胞可塑性的显着变化。这种现象代表了驱动心脏病形态和生理重塑的分子基础，并且可能包括旨在减轻疾病引起的重塑的适应不良和补偿机制。然而，在基因表达中执行这些变化，染色质结构必须发生显着改变才能沉默或激活基因组的选定区域。然而，最近对小鼠心脏肥大模型的研究表明，调节关键的表观遗传因子可以抑制这些基因表达变化并防止病理重塑。，我们对导致心脏病的染色质修饰剂的了解相当有限，Smyd1 是一种心肌细胞特异性组蛋白甲基转移酶，最初被确定为组成型 Smyd1 心脏发育的必要调节因子。最近，我们的敲除实验表明，在小鼠压力超负荷肥大和衰竭期间，Smyd1 的表达受到差异性调节（与其在人类中的表达一致），并且它控制着成人心脏中的病理基因表达和肌细胞生长。分离的肌细胞表明 Smyd1a 变体的过度表达可以抑制疾病诱导的重塑，这表明该途径可能有望成为治疗靶向尽管有这些发现，但人们对它知之甚少。 Smyd1 在成人心肌中的分子功能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从概念上增进我们对心力衰竭的理解。抑制肥大和衰竭动物模型中的生长和病理重塑，并确定控制 Smyd1 活性、基因组靶向和功能变异的因素。此外，这项工作将最终确定 Smyd1 如何调节生长。通过识别 Smyd1 结合的基因，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和心脏提供范式改变的见解。最终，表征这种新型心肌细胞特异性信号通路的组成部分可以揭示心力衰竭的新治疗靶点。