Epigenomic Mechanisms of Heart Failure

 描述(申请人提供)：要使个性化基因组医学成为现实，必须做两件事：第一，我们需要直接确定遗传变异在疾病发生和发展中的作用，而不是孤立地研究遗传关联和分子机制。其次，我们必须调查导致心血管疾病等复杂疾病的生物分子网络，作为紧急分子表型，同时使用有针对性的策略来建立因果关系。综上所述，这些创新可以帮助理解遗传变异如何与环境刺激相结合来影响疾病易感性。这项多重PI资助的目标是推动基因组药物治疗常见形式的心力衰竭。在动物和人类中，基因表达的全球变化伴随着心肌肥大和衰竭的过渡，导致细胞重塑和心功能恶化。我们推断，来自初级DNA序列的线索、DNA的修饰(即甲基化)、染色质相关蛋白(例如CTCF)和非编码RNA(例如C5)结合在一起指定了基因组结构，从而决定了基因的表达。在这个模型中，基因组构象通过有利于某些基因/蛋白质表达谱而不利于其他基因/蛋白表达谱来决定个体在病理刺激下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，并受到遗传和环境刺激的影响，因此一些人比其他人更容易发生心力衰竭。我们推测，染色质可及性的全球调节因子，包括新的表观遗传修饰物C5和结构蛋白CTCF，在疾病相关基因重新编程中发挥着核心作用。在第一个目标中，我们将通过解剖正常和应激心脏中对DNA甲基化(BS-SEQ)和染色质可及性(FIRE-SEQ)的遗传贡献，确定转录是如何受到基因局部染色质景观的调控的。在第二个目标中，我们将通过探索心脏特异的lncRNAC5在靶向异染色组蛋白修饰的沉积中的作用，来确定中间染色质结构域在心力衰竭中是如何调节的。在第三个目标中，我们将通过确定主基因组结构蛋白CTCF在心脏表型中的参与来确定全球染色质构象在心脏健康和疾病中的机制。这些研究的长期目标是确定基因变异如何控制不同疾病易感性的机制，并调查表观基因组学特征作为心脏病理的生物标志物和细胞功能障碍的原因成分。

 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.