AHA award letter MRG.pdf (584.51 kB)
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posted on 2019-03-05, 17:23 authored by Manuel Rosa-GarridoPrevious 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.