Ciceri, Gabriele;
Baggiolini, Arianna;
Cho, Hyein S;
Kshirsagar, Meghana;
Benito-Kwiecinski, Silvia;
Walsh, Ryan M;
Aromolaran, Kelly A;
... Studer, Lorenz; + view all
(2024)
An epigenetic barrier sets the timing of human neuronal maturation.
Nature
, 626
pp. 881-890.
10.1038/s41586-023-06984-8.
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Abstract
The pace of human brain development is highly protracted compared with most other species. The maturation of cortical neurons is particularly slow, taking months to years to develop adult function. 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 brain. 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.
| Type: | Article |
|---|---|
| Title: | An epigenetic barrier sets the timing of human neuronal maturation |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41586-023-06984-8 |
| Publisher version: | https://doi.org/10.1038/s41586-023-06984-8 |
| Language: | English |
| Additional information: | © The Author(s), 2024. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Neural stem cells, Neuronal development, Stem-cell biotechnology, Stem-cell differentiation |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10203727 |
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