The transcription factor Zeb1 in the heart

• Applicant: Dr. Vivien Kmietczyk
• Subject Area: Cardiology, Angiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 552055378

Zinc finger E-box binding homeobox 1 (Zeb1) is a versatile transcription factor involved in vital cellular processes, notably epithelial to mesenchymal transition (EMT), crucial in development and cancer metastasis. Zeb1 functions as both transcitpional activator and repressor. Studies in cancer cells and knockout mice reveal its influence on epithelial differentiation, cellular adhesion, and embryonic development. The knowledge about Zeb1's role in cardiovascular development and disease is emerging, particularly in cardiomyocyte differentiation. However, the function in the adult diseased heart is mainly unknown. Specifically, the target genes, mode of regulation of Zeb1, and consequences of Zeb1 activity on cardiac function in response to pathological stress remain to be determined. Our research indicates Zeb1 upregulation in stressed cardiomyocytes, impacting cellular remodeling, myofibrillar structure, and mitochondrial content, potentially affecting cardiac function. Experiments in isolated cardiomyocytes and knockout mouse models demonstrate Zeb1's significance in cardiac pathology. Transcriptomic analysis reveals Zeb1 dependent regulation of genes involved in mitochondrial function, sarcomere assembly, and extracellular matrix organization. This proposal aims to elucidate Zeb1's role in cardiomyocyte function, remodeling, and its target genes, offering insights into cardiac pathophysiology and therapeutic opportunities. With this proposal we seek to investigate how Zeb1 regulates cardiomyocyte function, particularly focusing on sarcomere integrity, mitochondrial homeostasis, and its role in cardiac remodeling. Additionally, we aim to understand the impact of Zeb1 dysregulation in heart failure progression and identify its target genes linked to cardiomyocyte function. Through three specific aims, we intend to provide comprehensive insights into Zeb1's role in postnatal cardiomyocyte maturation, pathological remodeling after pressure overload, and the identification of Zeb1 target genes crucial for cardiac function.

• DFG Programme: Research Grants