Epigenetic-metabolic axis in the temporal scaling of mammalian cortical neurogenesis across species

Developmental timescales vary widely across species, with mammalian cortical neurogenesis ranging from just days to several months. Given the conserved laminar architecture and regulatory gene expression sequences, the underlying molecular mechanisms controlling neurogenesis rate remain unknown. Using mouse, ferret, and human models, we combined comparative transcriptomics with mathematical modelling to identify conditions that scale temporal gene expression programs during neurogenesis. We show that H3K27me3-mediated repression is critical for maintaining species-specific neurogenesis timescales, and its ablation scales down neurogenesis duration. Furthermore, we identified the tricarboxylic-acid (TCA)-cycle metabolite -ketoglutarate as a modulator of developmental timing via H3K27me3 demethylation. Together, our findings link epigenetic and metabolic states to the control of species-specific developmental timescales and, ultimately, brain size.