While changes in chromatin modifications and gene expression are well characterized in eukaryotic development, the role of global chromatin remodeling in the setting of complex diseases is not understood. Common diseases like cardiovascular disease are the result of interplay between common genetic variation and environmental factors—they are also the leading causes of death worldwide. A better understanding of the molecular events that cause these diseases offers great potential to impact human health. Our group seeks to understand the basic principles for genome packaging and regulation in the adult heart, in particular, in the cardiac myocyte, which is a non-dividing cell that is multi-nucleated and whose genome is largely heterochromatic. The approaches we are taking in mouse models include in vivo imaging of global chromatin patterns (on the scale of the whole genome and individual chromosomes, using DAPI and fluorescence in situ hybridization, FISH) as well as investigation of specific loci for genes operative in the cardiac myocyte (using FISH and real-time transcription assays). In parallel studies, we are using sequencing-based genomics experiments, including chromatin immunoprecipitation and bisulfite sequencing, to investigate the role of specific proteins and DNA methylation, respectively, in the regulation of cardiac gene expression. The dynamics of chromatin rearrangement during disease are being investigated using pressure overload and isoproterenol (beta-adrenergic receptor agonist) models of cardiac hypertrophy and failure. Our studies are revealing the principles for cardiac-specific genome packaging and transcriptome regulation, identifying novel molecular mechanisms that causally impact the response of the heart to injury. Furthermore, by investigating the role of genetic diversity in chromatin structure, we have identified features of the epigenome that may be predictive of disease severity prior to environmental insult. The goal of these studies is to understand the logic for genome packaging in the adult heart and to use this knowledge to design diagnostic and therapeutic strategies for heart failure.