Epigenomic Mechanisms of Heart Failure

心力衰竭的表观基因组机制

• 批准号: 9119855
• 负责人: Thomas M. Vondriska
• 金额: $ 65.64万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-04 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9119855
• 关键词: Adult; Animals; Antisense RNA; Biological; Biological Assay; Biological Markers; CCCTC-binding factor; Cardiac; Cardiac health; Cardiovascular Diseases; Cell model; ChIP-seq; Chromatin; Chromatin Structure; Complex; Cues; DNA; DNA Methylation; DNA Modification Process; DNA Sequence; Deposition; Deterioration; Disease; Disease susceptibility; Environmental Risk Factor; Epigenetic Process; FAIRE sequencing; Failure; Figs - dietary; Functional disorder; Gene Expression; Gene Proteins; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Genetic Variation; Genome; Genomic medicine; Genomics; Genotype; Global Change; Goals; Grant; Health; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Histones; Human; Hybrids; Hypertrophy; Incidence; Individual; Investigation; Isoproterenol; Knock-out; Lead; Maps; Measures; Methylation; Modeling; Molecular; Molecular Conformation; Molecular Profiling; Mouse Strains; Mus; Pathology; Pattern; Phenotype; Play; Predisposition; Proteins; Proteomics; Regulation; Resistance; Resolution; Resources; Role; SPT6 Protein; Scourge; Stimulus; Stress; Structural Genes; Structure; Syndrome; Technology; Testing; To specify; Untranslated RNA; bisulfite sequencing; chromosome conformation capture; design; epigenome; epigenomics; genetic association; genome-wide; histone modification; in vivo; innovation; instrument; loss of function; methylome; molecular phenotype; novel; novel strategies; personalized genomic medicine; protein expression; time use; trait

 DESCRIPTION (provided by applicant): For personalized genomic medicine to be a reality, two things must happen: First, we need to directly establish the role of genetic variation in disease incidence and progression, rather than studying genetic associations and molecular mechanisms in isolation from each other. Second, we must investigate the networks of biological molecules responsible for complex diseases like cardiovascular disease as emergent molecular phenotypes, while at the same time using targeted strategies to establish causal relationships. Together, these innovations can lead to an understanding of how genetic variability combines with environmental stimuli to influence disease susceptibility. The goal of this multi-PI grant is to advance the field toward genomic medicine for common forms of heart failure. It is well established that global changes in gene expression accompany the transition through cardiac hypertrophy and on to failure in animals and humans, causing cellular remodeling and deterioration of cardiac function. We reason that cues from the primary DNA sequence, modification of DNA (i.e. methylation) and chromatin-associated proteins (e.g. CTCF) and noncoding RNA (e.g. C5) combine to specify genomic structure and thereby gene expression. In this model, genomic conformation determines the range of phenotypic possibilities in an individual subjected to pathological stimuli by favoring some gene/protein expression profiles and disfavoring others. Our overall hypothesis is that epigenomic features, including DNA methylation and chromatin accessibility, set the baseline plasticity of chromatin structure and are influenced by genetics and environmental stimuli, such that some individuals are more susceptible than others to heart failure. We reason that global regulators of chromatin accessibility, including the novel epigenetic modifier C5 and the structural protein CTCF, play central roles in disease associated gene reprogramming. In the first aim, we will identify how transcription is regulated by the local chromatin landscape at genes, by dissecting the genetic contribution to DNA methylation (BS-seq) and chromatin accessibility (FAIRE- seq) in the normal and stressed heart. In the second aim, we will determine how intermediate chromatin domains are regulated in heart failure by exploring the role of a cardiac-specific lncRNA C5 to target deposition of heterochromatic histone modifications. In the third aim, we will identify the mechanisms of global chromatin conformation in cardiac health and disease by determining the involvement of the master genome architectural protein CTCF in cardiac phenotype. The long-term goals of these studies are to determine the mechanisms for how genetic variation controls differential disease susceptibility and to investigate epigenomic features as both biomarkers for cardiac pathology and causal components of cellular dysfunction.

 描述（由适用提供）：要使个性化的基因组医学成为现实，必须发生两件事：首先，我们需要直接确定遗传变异在疾病发病率和进展中的作用，而不是研究遗传关联和分子机制在彼此隔离中的作用。其次，我们必须研究负责复杂疾病（如心血管疾病）作为紧急分子表型等复杂疾病的生物分子网络，同时使用有针对性的策略来建立灾难性关系。这些创新在一起可以使人们了解遗传变异性与环境刺激如何影响疾病易感性。这项多PI赠款的目的是向常见的心力衰竭迈向基因组医学的领域。众所周知，基因表达的全球变化涉及通过心脏肥大的过渡以及动物和人类的失败，从而导致细胞重塑并确定心脏功能。我们认为，从主要DNA序列，DNA（即甲基化）和染色质相关蛋白（例如CTCF）和非编码RNA（例如C5）组合结合以指定基因组结构及其基因表达的无编码RNA（例如C5）的提示。在此模型中，基因组构象通过偏爱某些基因/蛋白质表达谱并不利于其他人来确定受病理刺激的个体的表型可能性的范围。我们的总体假设是，包括DNA甲基化和染色质的可及性在内的表观基因组特征设定了染色质结构的基线可塑性，并受到遗传学和环境刺激的影响，因此某些人比其他人更容易受到心力衰竭。我们认为，包括新型表观遗传修饰剂C5和结构蛋白CTCF在内的染色质可及性的全球调节剂在相关的基因重编程中起着核心作用。在第一个目的中，我们将通过在正常和压力心脏中解剖遗传贡献对DNA甲基化（BS-SEQ）和染色质可及性（Faire-seq）的遗传贡献，从而确定转录如何受到基因处局部染色质景观的调节。在第二个目标中，我们将通过探索心脏特异性lncRNA C5在靶标沉积异型组蛋白修饰方面的作用来确定中间染色质结构域在心力衰竭中如何受到调节。在第三个目标中，我们将通过确定主基因组建筑蛋白CTCF参与心脏表型中的心脏健康和疾病中全球染色质构象的机制。这些研究的长期目标是确定遗传变异如何控制差异疾病易感性的机制，并研究表观基因组特征作为心脏病理学和细胞功能障碍的因果成分的生物标志物。