The study investigates the mechanisms underlying the prolonged maturation of human cortical neurons, which is a key feature of human brain development compared to other species. The authors developed a novel approach to synchronize the differentiation of human pluripotent stem cell (hPSC)-derived cortical neurons in vitro, allowing them to track the maturation process over several months. They found that the maturation of these neurons is regulated by an epigenetic barrier, which sets the pace of neuronal maturation. This barrier is established during the differentiation of progenitor cells (NPCs) and involves the retention of specific epigenetic factors. By transiently inhibiting key epigenetic factors such as EZH2, EHMT1, EHMT2, and DOTIL at the NPC stage, the authors were able to prime the neurons for accelerated maturation. This finding suggests that the rate at which human neurons mature is set before neurogenesis through the establishment of an epigenetic barrier in progenitor cells. The study also highlights the importance of these factors in maintaining the poised state of maturation programs, ensuring the prolonged timeline of human cortical neuron maturation.The study investigates the mechanisms underlying the prolonged maturation of human cortical neurons, which is a key feature of human brain development compared to other species. The authors developed a novel approach to synchronize the differentiation of human pluripotent stem cell (hPSC)-derived cortical neurons in vitro, allowing them to track the maturation process over several months. They found that the maturation of these neurons is regulated by an epigenetic barrier, which sets the pace of neuronal maturation. This barrier is established during the differentiation of progenitor cells (NPCs) and involves the retention of specific epigenetic factors. By transiently inhibiting key epigenetic factors such as EZH2, EHMT1, EHMT2, and DOTIL at the NPC stage, the authors were able to prime the neurons for accelerated maturation. This finding suggests that the rate at which human neurons mature is set before neurogenesis through the establishment of an epigenetic barrier in progenitor cells. The study also highlights the importance of these factors in maintaining the poised state of maturation programs, ensuring the prolonged timeline of human cortical neuron maturation.