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- W4387621152 abstract "Heart failure is a critical health issue that causes one in nine deaths in the United States. Despite extensive research on gene expression dynamics in the failing myocardium, the mechanisms by which the genome reorganizes itself to reconfigure transcription are poorly understood. CTCF is a crucial protein in chromatin architecture that mediates chromatin looping, acts as an enhancer insulator, and can function as either an activator or repressor of transcription. Our previous research indicates that CTCF plays a crucial role in heart failure, as cardiac-specific knockout of this protein promotes genome organization defects that result in cardiac pathology marked by reduced ejection fraction. To determine whether restoring CTCF levels could reverse this phenotype, we designed an AAV9 vector in which the cardiomyocyte-specific Troponin T promoter drives the expression of CTCF and GFP. Our results show that reintroduction of CTCF into failing CTCF-depleted mouse hearts successfully rescues the pathological phenotype of the animals, characterized by sustained improvement in ejection fraction and left ventricular chamber size in both systole and diastole. Furthermore, RNA-seq experiments reveal numerous differentially expressed genes with opposite transcriptional behavior depending on CTCF levels, including genes involved in chromatin organization (e.g., CHmgb2, Brca1, Smyd2), development of hypertrophy (e.g., Mef2a, Gata4, Mybpc3), extracellular matrix organization (e.g., Adamts5, Itgb1, Vtn) and collagen deposition (e.g., Col5a1, Col5a3). We also examined chromatin architecture through Hi-C experiments and discovered that restoration of CTCF levels remodels the global architecture of chromatin to closely resemble healthy myocyte chromatin. This finding supports the hypothesis that rescue of CTCF levels ameliorates cardiac disease by reverting the observed pathological gene expression profile through genomic reorganization. In summary, our project highlights the crucial role of CTCF in heart failure and demonstrates that structural repair of chromatin organization through modulation of CTCF levels is a novel and realistic approach to treating heart failure." @default.
- W4387621152 created "2023-10-14" @default.
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- W4387621152 date "2023-08-04" @default.
- W4387621152 modified "2023-10-15" @default.
- W4387621152 title "Abstract P1139: Remodeling Chromatin Structure To Induce And Reverse Heart Failure" @default.
- W4387621152 doi "https://doi.org/10.1161/res.133.suppl_1.p1139" @default.
- W4387621152 hasPublicationYear "2023" @default.
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