An epigenetic barrier sets the timing of human neuronal maturation

Gabriele Ciceri (), Arianna Baggiolini, Hyein S. Cho, Meghana Kshirsagar, Silvia Benito-Kwiecinski, Ryan M. Walsh, Kelly A. Aromolaran, Alberto J. Gonzalez-Hernandez, Hermany Munguba, So Yeon Koo, Nan Xu, Kaylin J. Sevilla, Peter A. Goldstein, Joshua Levitz, Christina S. Leslie, Richard P. Koche and Lorenz Studer ()
Additional contact information
Gabriele Ciceri: Memorial Sloan Kettering Cancer Center
Arianna Baggiolini: Memorial Sloan Kettering Cancer Center
Hyein S. Cho: Memorial Sloan Kettering Cancer Center
Meghana Kshirsagar: Memorial Sloan Kettering Cancer Center
Silvia Benito-Kwiecinski: Memorial Sloan Kettering Cancer Center
Ryan M. Walsh: Memorial Sloan Kettering Cancer Center
Kelly A. Aromolaran: Weill Cornell Medicine
Alberto J. Gonzalez-Hernandez: Weill Cornell Medicine
Hermany Munguba: Weill Cornell Medicine
So Yeon Koo: Memorial Sloan Kettering Cancer Center
Nan Xu: Memorial Sloan Kettering Cancer Center
Kaylin J. Sevilla: Memorial Sloan Kettering Cancer Center
Peter A. Goldstein: Weill Cornell Medicine
Joshua Levitz: Weill Cornell Medicine
Christina S. Leslie: Memorial Sloan Kettering Cancer Center
Richard P. Koche: Memorial Sloan Kettering Cancer Center
Lorenz Studer: Memorial Sloan Kettering Cancer Center

Nature, 2024, vol. 626, issue 8000, 881-890

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41586-023-06984-8

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