PIF2025 - Interacción entre Epigenética y Metabolismo en Neurogénesis Temprana:Descubriendo el Papel Central de la Desmetilasa de Histonas PHF8 - (PID2024-156081NB-I00)

The interplay between the epigenome, metabolism, and development is a cutting-edge field critical to understanding both normal development and disease. A key challenge is deciphering how genome activity is influenced by specific metabolites. While is recognized that covalent chromatin modifications, are directly influenced by the availability of epigenetic metabolites, the dynamic interaction between metabolic pathways and epigenetic regulation remains poorly understood. Unraveling these mechanisms could uncover fundamental principles of cellular function and offer transformative insights into disease biology. In our laboratory, we have been addressing this problem, by identifying the demethylase PHF8 as key regulator of progenitor proliferation whose deficiency disrupts epigenetic metabolite levels and metabolic enzyme expression, suggesting that PHF8 may act as a critical metabolic sensor during neural progenitor expansion. This project aims to unravel the connections between the epigenome and nuclear metabolism during neural stem cells proliferation by dissecting the metabolic role of PHF8. Specifically, we seek to identify the PHF8-dependent metabolic alterations during neural stem cell proliferation and elucidate the underlying molecular mechanisms. Additionally, we will validate the relevance of these metabolic changes in human progenitor cells and explore their potential contribution to the molecular etiology of Siderius-Hamel syndrome, caused by PHF8 deficiency.