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AHA award letter MRG.pdf (584.51 kB)

AHA award letter MRG.pdf

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posted on 2019-03-05, 17:23 authored by Manuel Rosa-Garrido
Previous work had suggested that cardiovascular disease was the result of aberrant epigenetic mechanisms, although the proteins altering the behavior of the cardiac genome were unknown. In this study we observed that CTCF levels were altered across a population of genetically distinct mice (which in turn exhibit a spectrum of phenotypic responses to pathologic stimuli associated with heart failure). To comprehensively determine CTCF’s function in the normal and diseased heart, we generated the first cardiac specific CTCF KO mouse, which enables selective removal of CTCF from the adult heart. Using this mouse model and performing Hi-C (Chromosome Conformation Capture followed by DNA sequencing), we have shown that loss of CTCF is sufficient to induce heart failure through mechanisms that involve restructuring of the genome. These studies answer a long-standing question in cardiac biology: what are the cell type specific changes that alter the expression of DNA to induce heart failure? Rather than individual genes, which we know are insufficient to reverse the syndrome of heart failure, CTCF commands an entire cadre of cardioprotective genes and molecules, maintaining appropriate function of the cardiac cell. When this protein is removed in disease, havoc ensues, leading to dysfunction of the organ at multiple levels. My studies show that CTCF plays a central role in cardiac-specific genome regulation and immediately suggest therapeutic avenues to modulate the epigenetic actions of CTCF to halt heart failure progression and to improve the functional capacity of cardiac muscle, thereby restoring health to sick patients.


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    American Heart Association



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