An epigenetic barrier sets the timing of human neuronal maturation Journal Article
| Authors: | Ciceri, G.; Baggiolini, A.; Cho, H. S.; Kshirsagar, M.; Benito-Kwiecinski, S.; Walsh, R. M.; Aromolaran, K. A.; Gonzalez-Hernandez, A. J.; Munguba, H.; Koo, S. Y.; Xu, N.; Sevilla, K. J.; Goldstein, P. A.; Levitz, J.; Leslie, C. S.; Koche, R. P.; Studer, L. |
| Article Title: | An epigenetic barrier sets the timing of human neuronal maturation |
| Abstract: | The slow maturation of human neurons is regulated by epigenetic modification in nascent neurons, mediated by EZH2, EHMT1, EHMT2 and DOT1L. © The Author(s) 2024.; 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 Author(s) 2024. |
| Keywords: | adult; controlled study; human tissue; human cell; nonhuman; genetic analysis; animal cell; mouse; animal; animals; mice; animal tissue; gene; gene expression; embryo; animal experiment; cell differentiation; neurons; in vitro study; physiology; epigenesis, genetic; histone-lysine n-methyltransferase; brain development; fetus; pluripotent stem cell; pluripotent stem cells; nervous system development; neurogenesis; nerve cell; genetic epigenesis; histone lysine methyltransferase; cell; maturation; histocompatibility antigens; brain cell; histocompatibility antigen; ehmt2 protein, human; humans; human; male; article; first cervical vertebra |
| Journal Title: | Nature |
| Volume: | 626 |
| Issue: | 8000 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-02-22 |
| Start Page: | 881 |
| End Page: | 890 |
| Language: | English |
| DOI: | 10.1038/s41586-023-06984-8 |
| PUBMED: | 38297124 |
| PROVIDER: | scopus |
| PMCID: | PMC10881400 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Gabriele Ciceri -- Source: Scopus |
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