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Pereira, A. ; Diwakar, S.J. ; Masserdotti, G. ; Beşkardeş, S. ; Simon, T. ; So, Y. ; Martín-Loarte, L. ; Bergemann, F. ; Vasan, L.* ; Schauer, T. ; Danese, A. ; Bocchi, R. ; Colomé-Tatché, M. ; Schuurmans, C.* ; Philpott, A.* ; Straub, T.* ; Bonev, B. ; Götz, M.

Direct neuronal reprogramming of mouse astrocytes is associated with multiscale epigenome remodeling and requires Yy1.

Nat. Neurosci. 27, 1260–1273 (2024)

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Direct neuronal reprogramming is a promising approach to regenerate neurons from local glial cells. However, mechanisms of epigenome remodeling and co-factors facilitating this process are unclear. In this study, we combined single-cell multiomics with genome-wide profiling of three-dimensional nuclear architecture and DNA methylation in mouse astrocyte-to-neuron reprogramming mediated by Neurogenin2 (Ngn2) and its phosphorylation-resistant form (PmutNgn2), respectively. We show that Ngn2 drives multilayered chromatin remodeling at dynamic enhancer-gene interaction sites. PmutNgn2 leads to higher reprogramming efficiency and enhances epigenetic remodeling associated with neuronal maturation. However, the differences in binding sites or downstream gene activation cannot fully explain this effect. Instead, we identified Yy1, a transcriptional co-factor recruited by direct interaction with Ngn2 to its target sites. Upon deletion of Yy1, activation of neuronal enhancers, genes and ultimately reprogramming are impaired without affecting Ngn2 binding. Thus, our work highlights the key role of interactors of proneural factors in direct neuronal reprogramming.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Cell; Differentiation; Mechanisms; Dynamics; Fibroblast; State

ISSN (print) / ISBN 1097-6256

e-ISSN 1546-1726

Journal Nature Neuroscience

Quellenangaben Volume: 27, Pages: 1260–1273

Publisher Nature Publishing Group

Publishing Place Heidelberger Platz 3, Berlin, 14197, Germany

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Stem Cell Research (ISF)
Helmholtz Pioneer Campus (HPC)
Institute of Epigenetics and Stem Cells (IES)
Institute of Computational Biology (ICB)

Grants UKRI Medical Research Council
European Union
ERA-NET Neuron (MOSAIC)
European Research Council
Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada and Social Sciences and Humanities Research Council of Canada
Wellcome Trust
Cancer Research UK
German Research Foundation