ZEB1 Is a Key Regulator of Cardiomyocyte Structure and Function

Background: The structure and function of cardiomyocytes rely on tightly regulated gene networks that control development, maturation, and homeostasis. Disruption of these networks is associated with cardiomyopathies such as hypertrophic and dilated cardiomyopathy, leading to heart failure. Our previous work identified the transcription factor "Zinc Finger E-Box Binding Homeobox 1" (ZEB1) as a downstream effector of Cytoplasmic Polyadenylation Element Binding Protein 4 (CPEB4), an RNA-binding protein responsive to cardiac stress. While ZEB1 is known for its role in cancer metastasis and epithelial-to-mesenchymal transition (EMT), its function in cardiomyocytes is not well understood. Based on previous findings, we hypothesize that ZEB1 is essential for maintaining the structural integrity and contractile function of cardiomyocytes. Hypothesis and objectives: We hypothesized that ZEB1 plays a critical role in maintaining cardiomyocyte structure and function. Deletion of Zeb1 may result in sarcomeric disorganization and mitochondrial dysfunction, whereas its overexpression appears to promote maladaptive hypertrophy. Our objectives are to: 1. Investigate if ZEB1 overexpression induces pathological cardiac remodeling. 2. Examine the effects of ZEB1 deletion on cardiomyocyte structure and function. 3. Identify ZEB1-regulated transcriptional networks. Methods: AAV9-ZEB1 was used for the overexpression of ZEB1. Using a myosin heavy chain alpha ( -MHC) Cre system, we created a ZEB1 conditional knockout mouse. To evaluate the cardiac function, we used methods like echocardiography, electron microscopy, immunohistochemistry. We identified differential expressed genes upon deletion of Zeb1 using RNA-seq and integrated the data set with ChIP-seq. Results: ZEB1 deletion leads to sarcomere damage, mitochondrial dysfunction, and dedifferentiation, with more pronounced effects in females. Overexpression promotes hypertrophic remodeling. Echocardiographic analysis showed progressive systolic dysfunction, and histology revealed sarcomeric disarray, again especially in females. A tamoxifen-inducible ZEB1 knockout mouse model confirmed ZEB1's crucial role in fully differentiated cardiomyocytes. Conclusions: ZEB1 is critical for cardiomyocyte homeostasis, and maintaining its function is necessary for normal cardiac performance and structure.