Epigenetic Regulation of Serine Biosynthesis by PHF8 During Neurogenesis

During neurodevelopment, progenitor proliferation is a highly orchestrated process, involving precise epigenetic modifications and immense metabolic demands. Yet, the intricate interplay between epigenetics and metabolism remains largely unexplored. To investigate this, we utilized neural stem cells to examine 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. Notably, loss of PHF8 not only disrupts amino acid metabolism and mTORC1 signaling, but also blocks autophagic flux, and impairs vesicle formation—ultimately stalling proliferation and triggering replicative defects and DNA damage. In vivo, PHF8 deficiency in mouse embryos halts neurogenesis, affecting progenitor expansion and neuron generation in the developing brain. Altogether, our work positions PHF8 as a pivotal molecular node linking chromatin dynamics, metabolic regulation, and neural development. These findings not only deepen our understanding of brain development but also open new avenues for exploring the epigenetic basis of metabolic and neurodevelopmental disorders.