Epigenetic regulation of serine biosynthesis by PHF8 during neurogenesis

Progenitor proliferation during neurodevelopment requires tight coordination of epigenetic regulation and metabolism. However, the crosstalk between these processes remains poorly understood. To investigate this, we examine in neural stem cells the role of PHF8, a histone demethylase whose mutations are linked to Siderius-Hamel syndrome, a rare neurodevelopmental disorder. Through an integrated multi-omics approach - combining transcriptomics, epigenomics, and metabolomics - we identify PHF8 as a key driver of the serine biosynthesis pathway, safeguarding the intracellular serine pool essential for neural progenitor proliferation. PHF8 fine-tunes chromatin accessibility at promoters of metabolic genes, ensuring their activation during development. Loss of PHF8 disrupts amino acid metabolism, blocks autophagy, and hinders vesicle formation. Ultimately PHF8 depletion leads to replication defects, DNA damage, and proliferation arrest. In vivo, PHF8 deficiency in mouse embryos halts neurogenesis, progenitor expansion, and neuron generation in the developing brain. These findings identify PHF8 as a key molecular link between chromatin regulation, metabolic control, and neural development, offering new insights into the epigenetic basis of neurodevelopmental and metabolic disorders.