Functional Characterization of the Cardiac Development of A rrhythmias and Dysfunction: Role of Chd4, Znf219 and ThPOK interaction

• Autores: Fadoua El Abdellaoui Souss
• Directores de la Tesis: Pablo Gómez del Arco (dir. tes.), Juan Miguel Redondo Moya (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2023
• Idioma: inglés
• Número de páginas: 172
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • The physiological function of adult cardiomyocytes depends largely on the fine regulation of gene expression during both development and adulthood. For adequate contraction, myocardium-specific actomyosin complexes must be assembled, forming cross-bridges, which subsequently generate sufficient energy to propel blood to the rest of the organism. This too allows tissue relaxation during the refractory period, thus avoiding myocardial tetanization. A regulator of cardiomyocyte gene expression is the chromatin remodeler Chd4/NuRD, which maintains cardiac muscle identity by repressing the expression of skeletal muscle sarcomeric genes. In the absence of Chd4/ N uRD, cardiomyocytes are thus “hybrid myocytes”, containing both cardiac and skelet al myofibril components. These aberrantly expressed proteins intercalate in the cardiac sarcomere causing impairment of cardiac function, which translates to arrhythmias, fibrosis and ventricular dysfunction leading to sudden death. The identification of transcription factors (TFs) that recruit Chd4/NuRD to repress skeletal muscle genes in the myocardium is therefore seminal for understanding cardiac physiology. Alterations in these molecular interactions may unveil numerous cardiac pathologies and ultimately point to new therapeutic targets for arrhythmias and cardiomyopathies. In this thesis, we attempt to find and describe some of the TFs t hat genetically and/or physically interact with Chd4/NuRD, and their role in cardiac homeostasis. Thus, we first describe the synergistic transcriptional repression of the pro-apoptotic protein Sprr1a by Chd4 and the TF ThPOK, whose aberrant expression produces ventricular dysfunction and severe arrhythmias, such as atrial fibrillation and n on-sustained polymorphic ventricular fibrillation, ultimately resulting in heart failure a nd sudden death. We secondly describe a physical interaction between Chd4 and the TF Znf219 i n cardiac tissue. Znf219 represses in vitro and in vivo t he skeletal muscle sarcomeric program in cardiomyocytes, similarly to Chd4. Aberrant expression of skeletal muscle sarcomere proteins in Znf219-knockdown mouse hearts results in arrhythmias, accom - panied by an increased PR interval. These data strongly suggest that the physical and genetic interaction of Znf219 and Chd4 in the mammalian heart regulates cardiomyo - cyte identity and myocardial contraction