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Abstract

Cardiomyocyte function and survival rely on tightly controlled quality control systems that safeguard both nuclear integrity and cellular homeostasis. While the E3 ubiquitin ligase TRIM24 has been extensively studied in cancer and neurodegeneration, its role in the heart remained unclear. This dissertation presents a comprehensive characterization of TRIM24 in cardiomyocytes through genome-wide sequencing, targeted biochemical assays, and biophysical imaging techniques. These approaches revealed that TRIM24 modulates chromatin architecture and transcriptional regulation, thereby shaping gene expression programs relevant to cardiac function. Among these, TRIM24 was found to suppress inflammatory signaling in cardiomyocytes, extending its known immunomodulatory role into the cardiac context for the first time. Furthermore, the study identifies a novel function of TRIM24 in calcium handling and excitation-contraction coupling. By integrating super-resolution microscopy, functional calcium imaging, and contractility assays, the study demonstrates that TRIM24-dependent structural remodeling of calcium channel organization is associated with altered calcium cycling and measurable changes in cardiomyocyte contraction. Together, this work positions TRIM24 as a multifunctional regulator in cardiomyocytes, linking chromatinlevel control to physiological signaling pathways. These insights advance our understanding of cardiac proteostasis and may offer new therapeutic entry points for cardiovascular disease.