A study identifies an epigenetic barrier that sets the timing of human neuronal maturation. Human brain development is slower compared to most species, with cortical neurons taking months to years to mature. This slow maturation is retained in neurons derived from human pluripotent stem cells (hPSCs) in vitro or when transplanted into the mouse brain, suggesting an intrinsic clock controlling neuronal maturation. The researchers developed a method to synchronize the birth of cortical neurons from hPSCs, enabling the creation of an atlas of morphological, functional, and molecular maturation. They observed that maturation programs unfold slowly, limited by the retention of specific epigenetic factors. Loss of function of these factors in cortical neurons enables precocious maturation. Transient inhibition of EZH2, EHMT1, EHMT2, or DOT1L at the progenitor stage primes newly born neurons to rapidly acquire mature properties upon differentiation. The findings reveal that the rate of human neuron maturation is set before neurogenesis through the establishment of an epigenetic barrier in progenitor cells. Mechanistically, this barrier holds transcriptional maturation programs in a poised state that is gradually released to ensure the prolonged timeline of human cortical neuron maturation. The study also shows that the epigenetic barrier in progenitor cells (NPCs) sets the pace of maturation. Transient inhibition of key epigenetic factors (EZH2, DOT1L, and EHMT1/2) in NPCs enables accelerated post-mitotic neuronal maturation. The researchers found that several maturation-related genes are transcriptionally poised in NPCs via dual deposition of H3K27me3 and H3K4me3. Reducing H3K27me3 levels via EZH2 inhibition accelerated the subsequent expression of many maturation-related transcripts. The epigenetic barrier comprises multiple classes of chromatin regulators, and further studies will need to dissect their interplay. The study highlights the role of the epigenetic barrier in regulating the timing of neuronal maturation, with implications for understanding and modeling brain disorders. The findings suggest that the epigenetic barrier is a key factor in determining the protracted maturation of human neurons, and that manipulating this barrier could improve hPSC-based technologies for studying brain development and disease.A study identifies an epigenetic barrier that sets the timing of human neuronal maturation. Human brain development is slower compared to most species, with cortical neurons taking months to years to mature. This slow maturation is retained in neurons derived from human pluripotent stem cells (hPSCs) in vitro or when transplanted into the mouse brain, suggesting an intrinsic clock controlling neuronal maturation. The researchers developed a method to synchronize the birth of cortical neurons from hPSCs, enabling the creation of an atlas of morphological, functional, and molecular maturation. They observed that maturation programs unfold slowly, limited by the retention of specific epigenetic factors. Loss of function of these factors in cortical neurons enables precocious maturation. Transient inhibition of EZH2, EHMT1, EHMT2, or DOT1L at the progenitor stage primes newly born neurons to rapidly acquire mature properties upon differentiation. The findings reveal that the rate of human neuron maturation is set before neurogenesis through the establishment of an epigenetic barrier in progenitor cells. Mechanistically, this barrier holds transcriptional maturation programs in a poised state that is gradually released to ensure the prolonged timeline of human cortical neuron maturation. The study also shows that the epigenetic barrier in progenitor cells (NPCs) sets the pace of maturation. Transient inhibition of key epigenetic factors (EZH2, DOT1L, and EHMT1/2) in NPCs enables accelerated post-mitotic neuronal maturation. The researchers found that several maturation-related genes are transcriptionally poised in NPCs via dual deposition of H3K27me3 and H3K4me3. Reducing H3K27me3 levels via EZH2 inhibition accelerated the subsequent expression of many maturation-related transcripts. The epigenetic barrier comprises multiple classes of chromatin regulators, and further studies will need to dissect their interplay. The study highlights the role of the epigenetic barrier in regulating the timing of neuronal maturation, with implications for understanding and modeling brain disorders. The findings suggest that the epigenetic barrier is a key factor in determining the protracted maturation of human neurons, and that manipulating this barrier could improve hPSC-based technologies for studying brain development and disease.