Epigenetic Regulation of Serine Biosynthesis by PHF8 During Neurogenesis

During neurodevelopment, progenitor proliferation depends on epigenetic modifications and metabolic programs. We used neural stem cells to examine the role of PHF8, a histone demethylase linked to Siderius-Hamel syndrome, in neural development. Using a multi-omics approach that combines transcriptomics, epigenomics, and metabolomics, we identify PHF8 as a key driver of the serine biosynthesis pathway, modulating chromatin accessibility at metabolic gene promoters. Loss of PHF8 disrupts amino acid metabolism, mTORC1 signaling and autophagy, leading to replication defects and DNA damage. In vivo, PHF8 deficiency impaired neurogenesis. This work positions PHF8 as a pivotal molecular node linking chromatin dynamics, metabolic regulation, and neural development.