# Epigenetic regulation of serine biosynthesis by PHF8 during neurogenesis

## TL;DR

This study shows how PHF8, an epigenetic regulator, controls serine biosynthesis in neural stem cells, linking chromatin regulation to metabolism and neurodevelopment.

## Contribution

The study identifies PHF8 as a novel epigenetic-metabolic regulator in neural stem cells, connecting chromatin accessibility to serine biosynthesis and proliferation.

## Key findings

- PHF8 maintains chromatin accessibility at metabolic gene promoters, driving serine biosynthesis.
- Loss of PHF8 disrupts amino acid metabolism, autophagy, and vesicle formation in neural stem cells.
- PHF8 deficiency causes DNA damage, proliferation arrest, and halted neurogenesis in mouse embryos.

## Abstract

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.

PHF8 links chromatin regulation to metabolism in neural stem cells, driving serine biosynthesis and supporting proliferation. Its loss impairs amino acid metabolism, autophagy, and neurogenesis, revealing an epigenetic-metabolic axis underlying neurodevelopment.

PHF8 regulates neural progenitor proliferation by coordinating epigenetic and metabolic programsPHF8 drives serine biosynthesis and maintains chromatin accessibility of serine synthesis genes.Loss of PHF8 disrupts metabolism, autophagy, and vesicle formation.PHF8 deficiency leads to DNA damage and halts neurogenesis in vivo.

PHF8 regulates neural progenitor proliferation by coordinating epigenetic and metabolic programs

PHF8 drives serine biosynthesis and maintains chromatin accessibility of serine synthesis genes.

Loss of PHF8 disrupts metabolism, autophagy, and vesicle formation.

PHF8 deficiency leads to DNA damage and halts neurogenesis in vivo.

PHF8 links chromatin regulation to metabolism in neural stem cells, driving serine biosynthesis and supporting proliferation. Its loss impairs amino acid metabolism, autophagy, and neurogenesis, revealing an epigenetic-metabolic axis underlying neurodevelopment.