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Orchestration of Cardiac Gene Expression Mediated by Global Chromatin Architecture


The underlying mechanisms by which cell identity is achieved in a cell type-specific manner during development are unknown. In this project, we examine the mechanisms through which genomic architecture is regulated by different protein factors and how these proteins in turn regulate gene expression in the cardiomyocyte. We search for cardiac chromatin structural factors that are important for the establishment of genomic architecture during differentiation. We hypothesized that these candidates would also be implicated in pathological gene expression upon the onset of heart failure. Instead, we found that the expression changes of chromatin structural genes across a panel of different mouse strains were not universal, nor did they correlate with cardiac phenotype after pathological stress. Most of our current knowledge of signaling mechanisms in the heart has stemmed from genetic manipulations in a single mouse strain. Here, we examined well-characterized regulators of cardiac phenotype and showed that the relationships between gene expression and cardiac phenotype are lost when expanding across multiple genetic backgrounds. More importantly, these data demonstrate that there is no single signature gene that drives heart disease (nor is there a single gene whose expression is a biomarker of the condition), highlighting the role of genetic variability to differentially sculpt the transcriptome in the development and progression of complex diseases. In addition, our findings demonstrate that regulation of gene expression by genetics occurs in a tissue-dependent manner. We previously identified High Mobility Group B2 as an important chromatin structural protein in the heart and showed its involvement in pathological gene expression. These studies suggested this regulation occurs by remodeling global transcriptional activity. To characterize structural organization of cellular transcription, we show that transcriptional activity is compartmentalized into stable factories in the heart that undergo functional changes in vivo in response to disease stimuli. We provide evidence of direct reorganization of genomic structure by showing that nuclear positioning of cardiac genes with respect to chromatin environments and transcription factories correlates with changes in their expression. In summary, this project explores the mechanisms of cardiac gene regulation and illustrates multiple levels of regulation, with influences from genetics and chromatin architecture.

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