An epigenetic barrier sets the timing of human neuronal maturation

Abstract The pace of human brain development is highly protracted compared to most other species. The maturation of cortical neurons is particularly slow, extending over months to years to reach adult-like functions. Remarkably, such protracted timing is retained in cortical neurons derived from human pluripotent stem cell (hPSC) during in vitro differentiation or upon transplantation into the murine brain in vivo . Those findings suggest the presence of a cell intrinsic clock that sets the pace of neuronal maturation, though the molecular nature of such a clock has remained elusive. Here, we identify an epigenetic developmental program which sets the timing of human neuronal maturation. First, we developed a human PSC-based approach to synchronize the birth of cortical neurons in vitro which allowed us to define a detailed atlas of progressive morphological, functional, and molecular maturation in human cortical neurons. Interestingly, we observed a slow, temporal unfolding of maturation programs that is limited by the retention of a specific set of epigenetic factors. Loss-of-function studies for several of those factors in cortical neurons enables precocious molecular and physiological maturation. Remarkably, transient inhibition of EZH2, EHMT1/2 or DOT1L, at the progenitor stage primes newly born neurons to rapidly acquire mature properties upon differentiation. Therefore, our findings reveal that the rate at which human neurons mature is set well before neurogenesis through the establishment of an “epigenetic barrier” in progenitor cells. Mechanistically, this barrier acts by holding transcriptional maturation programs in a poised state that gets gradually released during neuronal differentiation to ensure the prolonged timeline characteristic of human cortical neuron maturation.