An epigenetic barrier sets the timing of human neuronal maturation

• 成果类型: Article
• 署名作者: Ciceri, Gabriele; Baggiolini, Arianna; Cho, Hyein S.; Kshirsagar, Meghana; Benito-Kwiecinski, Silvia; Walsh, Ryan M.; Aromolaran, Kelly A.; Gonzalez-Hernandez, Alberto J.; Munguba, Hermany; Koo, So Yeon; Xu, Nan; Sevilla, Kaylin J.; Goldstein, Peter A.; Levitz, Joshua; Leslie, Christina S.; Koche, Richard P.; Studer, Lorenz
• 署名单位: Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Universita della Svizzera Italiana; Institute of Oncology Research (IOR); Universita della Svizzera Italiana
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4747
• DOI: 10.1038/s41586-023-06984-8
• 发表日期: 2024-02-22
• 关键词: pluripotent stem-cells; functional maturation; pyramidal neurons; cortical-neurons; differentiation; inhibition; neurogenesis; cortex; models; interneurons

摘要

The pace of human brain development is highly protracted compared with most other species1-7. The maturation of cortical neurons is particularly slow, taking months to years to develop adult functions3-5. Remarkably, such protracted timing is retained in cortical neurons derived from human pluripotent stem cells (hPSCs) during in vitro differentiation or upon transplantation into the mouse brain4,8,9. Those findings suggest the presence of a cell-intrinsic clock setting the pace of neuronal maturation, although the molecular nature of this clock remains unknown. Here we identify an epigenetic developmental programme that sets the timing of human neuronal maturation. First, we developed a hPSC-based approach to synchronize the birth of cortical neurons in vitro which enabled us to define an atlas of morphological, functional and molecular maturation. We observed a slow unfolding of maturation programmes, limited by the retention of specific epigenetic factors. Loss of function of several of those factors in cortical neurons enables precocious maturation. Transient inhibition of EZH2, EHMT1 and EHMT2 or DOT1L, at progenitor stage primes newly born neurons to rapidly acquire mature properties upon differentiation. Thus 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 holds transcriptional maturation programmes in a poised state that is gradually released to ensure the prolonged timeline of human cortical neuron maturation. The slow maturation of human neurons is regulated by epigenetic modification in nascent neurons, mediated by EZH2, EHMT1, EHMT2 and DOT1L.