Reprogramming of cardiac genome by Smyd1 in hypertrophy and failure

Smyd1 在肥厚和衰竭中对心脏基因组进行重编程

• 批准号: 8535191
• 负责人: Sarah Franklin
• 金额: $ 23.63万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8535191
• 关键词: Address; Adult; Affect; Animals; Architecture; Attention; Binding; Biochemistry; Birth; Budgets; Cardiac; Cardiac Myocytes; Cause of Death; Cell model; Cells; Characteristics; Chromatin; Chromatin Structure; Clinical; Co-Immunoprecipitations; DNA; DNA Packaging; DNA Sequence; Data; Development; Disease; Embryo; Enzymes; Estrogen Receptors; Event; Excision; Exhibits; Failure; Family; Family member; Figs - dietary; Future; Gene Expression; Genes; Genome; Genomics; Goals; Grant; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Heat-Shock Proteins 90; Higher Order Chromatin Structure; Histone H3; Histones; Human; Hypertrophy; Image; Intervention; Life; Mass Spectrum Analysis; Measures; Messenger RNA; Methylation; Microscopy; Modification; Morphology; Mus; Muscle; Muscle Cells; Myoblasts; Myocardium; Nuclear; Nuclear Proteins; Nucleosomes; Performance; Phenotype; Physiology; Positioning Attribute; Post-Translational Protein Processing; Proteins; Proteomics; Regulation; Role; Site; Specificity; Stimulus; Tail; Tamoxifen; Technology; TimeLine; Transcript; Transgenic Mice; Western Blotting; base; cell type; chromatin remodeling; constriction; genome-wide; histone methyltransferase; in vivo; insight; next generation sequencing; overexpression; pressure

PROJECT SUMMARY/ABSTRACT It is now appreciated that genomes are dynamic and that selective packing of DNA governs the expression of distinct sets of genes in a cell. The wrapping of DNA around nucleosomes and its organization into higher order structures is fundamentally influenced by chromatin remodeling enzymes. These enzymes selectively position nucleosomes along the DNA strand and influence the interaction of histones with DNA by modifying the amino terminal tails of histones. Gross changes in chromatin structure are most prominent during development and influence cell fate by establishing cell-type-specific gene expression. Changes in chromatin structure have also been observed during disease and disruption of chromatin remodeling enzymes has been implicated in cardiac hypertrophy. However, a clear picture of the protein networks that modulate chromatin architecture in the heart is needed to understand how gene expression is reprogrammed on a genome-wide scale during disease. Although the post-translational modification (PTM) of histones has been well established, the enzymes responsible for the selective addition and removal of these regulatory marks have only begun to be characterized. A newly emerging family of histone methyltransferases (HMTs) is called Smyd. Germline deletion of the muscle-restricted family member, Smyd1, leads to embryonic lethality due to impaired cardiac differentiation. Consistent with this observation, overexpression of Smyd1 in muscle precursor cells led to accelerated differentiation. Despite these intriguing insights into the role of Smyd1 during development, its endogenous localization, regulation and role in cardiac disease are unknown. My preliminary data demonstrate increased Smyd1 abundance during heart failure and establish the approaches to determine its activity, intracellular localization and mechanisms of action in this application. The short term goal of this application is to understand the role of Smyd1 in the adult myocardium and to characterize its downstream targets during heart failure. The long term goal of this project is to integrate these concepts to understand the factors that confer targeting specificity to Smyd1 in the cardiac genome. This application leverages state-of-the-art proteomics, animal physiology, biochemistry, imaging and next generation sequencing technology to advance our understanding of heart failure. Our approach will provide fundamental insights into the activation and regulation of HMTs, as well as the mechanisms that confer specificity in their targeting of the genome. The significance to the clinical realm is to provide a mechanistic basis for how the genome is reprogrammed with disease, such that future interventions can target specific chromatin remodeling events therapeutically.

项目概要/摘要 现在人们认识到基因组是动态的，DNA 的选择性堆积控制着基因组的变化。 细胞中不同基因组的表达。 DNA 围绕核小体的包裹及其组织 高级结构从根本上受到染色质重塑酶的影响。 这些酶 沿着 DNA 链选择性地定位核小体，并通过以下方式影响组蛋白与 DNA 的相互作用 修饰组蛋白的氨基末端尾部。 染色质结构的总体变化在发育过程中最为突出，并影响细胞命运 通过建立细胞类型特异性基因表达。 还观察到染色质结构的变化 疾病期间染色质重塑酶的破坏与心脏肥大有关。 然而，需要了解调节心脏染色质结构的蛋白质网络的清晰图像 了解疾病期间基因表达如何在全基因组范围内重新编程。 尽管组蛋白的翻译后修饰 (PTM) 已得到充分证实，但酶 负责选择性添加和删除这些监管标记的机构才刚刚开始 特点。 一个新出现的组蛋白甲基转移酶 (HMT) 家族称为 Smyd。 种系 肌肉受限家族成员 Smyd1 的缺失会因心脏受损而导致胚胎死亡 差异化。 与这一观察结果一致，肌肉前体细胞中 Smyd1 的过度表达导致 加速分化。 尽管对 Smyd1 在发育过程中的作用有这些有趣的见解，但它 心脏病中的内源性定位、调节和作用尚不清楚。 我的初步数据 证明心力衰竭期间 Smyd1 丰度增加，并建立确定其的方法 本申请中的活性、细胞内定位和作用机制。 该应用的短期目标是了解 Smyd1 在成人心肌中的作用和 描述心力衰竭期间其下游目标的特征。 该项目的长期目标是整合 这些概念可帮助您了解赋予心脏基因组中 Smyd1 靶向特异性的因素。这 应用程序利用最先进的蛋白质组学、动物生理学、生物化学、成像等 世代测序技术可增进我们对心力衰竭的了解。我们的方法将提供 对 HMT 激活和调节的基本见解，以及赋予其作用的机制 他们针对基因组的特异性。 对临床领域的意义在于提供一种机制 基因组如何随疾病重新编程的基础，以便未来的干预措施可以针对特定的目标 治疗上的染色质重塑事件。