Obiettivo Understanding mechanisms underlying cardiomyocyte (CM) transcriptional regulation is critical for deciphering molecular origins of cardiac malformations. Epigenetics is crucial for stabilizing transcriptional programs, but little is known about the “epigenetic code” of histone methylation during cardiogenesis, and in particular the role of histone methylation at lysine 79 (H3K79me) during heart development. DOT1L is the sole enzyme that catalyzes methylation at H3K79. Different degrees of H3K79me lead to distinct transcriptional readouts (gene activation, repression, or no changes of transcription) in a context dependent manner. H3K79me fluctuates during development, with Dot1L expression being high in heart. My initial studies in mouse embryonic stem cell-derived CMs suggested that DOT1L is required at early stages of cardiogenesis. ChIP-seq results from neonatal and adult CMs show H3K79me2 enriched in genes encoding CM structural proteins and cell cycle regulators. The foregoing suggest a critical role in heart development, but the role of DOT1L and the specific functions of H3K79me during early CM development in vivo have not yet been studied. My preliminary data showed that early CM specific cKO of Dot1L, driven by xMLC2cre, results in lethality at P2, with a phenotype exhibiting increased CM proliferation, demonstrating an essential role for DOT1L in cardiogenesis and CM cell cycle regulation. My hypothesis is that DOT1L plays a key role in heart development, defining a H3K79 dependent epigenetic landscape essential for cardiogenesis and CM cell cycle regulation. To test this hypothesis, my Aims are: 1)To investigate effects of early CM-specific deletion of Dot1L on cardiac morphogenesis and CM cell biology 2)To identify genes directly regulated, by DOT1L mediated-H3K79me in vivo. Completion of these aims will define mechanisms by which DOT1L is required for cardiogenesis and cell cycle regulation, helping to design new therapies for congenital heart disease. Campo scientifico medical and health sciencesclinical medicinecardiologypaediatric cardiologynatural sciencesbiological sciencescell biologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymesnatural sciencesbiological sciencesgeneticsepigenetics Programma(i) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Argomento(i) FP7-PEOPLE-2013-IOF - Marie Curie Action: "International Outgoing Fellowships for Career Development" Invito a presentare proposte FP7-PEOPLE-2013-IOF Vedi altri progetti per questo bando Meccanismo di finanziamento MC-IOF - International Outgoing Fellowships (IOF) Coordinatore CONSIGLIO NAZIONALE DELLE RICERCHE Contributo UE € 261 175,80 Indirizzo PIAZZALE ALDO MORO 7 00185 Roma Italia Mostra sulla mappa Regione Centro (IT) Lazio Roma Tipo di attività Research Organisations Contatto amministrativo Gianluigi Condorelli (Prof.) Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato
