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—acting in the theater of the epigenome—to make us sick or keep us healthy.

The goal of our research is to advance the field toward genomic medicine for common forms of heart failure—a syndrome resulting from complex genetic predisposition and environmental/lifestyle factors. 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 and noncoding RNA molecules 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. 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 disease.

Our research uses targeted gain and loss of function studies in animal models, multiple ‘omics technologies in a discovery format and translational human studies to understand general principles of chromatin biology and to investigate how epigenomic features control cardiovascular health and disease.

Research Interests & Expertise: The epigenomic mechanisms of cardiovascular disease

Departments: Anesthesiology & Perioperative Medicine and Physiology

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