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De novo DNA methylation controls neuronal maturation during adult hippocampal neurogenesis

Adult neurogenesis enables the life‐long addition of functional neurons to the hippocampus and is regulated by both cell‐intrinsic molecular programs and behavioral activity. De novo DNA methylation is crucial for embryonic brain development, but its role during adult hippocampal neurogenesis has re...

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Autores principales: Zocher, Sara, Overall, Rupert W, Berdugo‐Vega, Gabriel, Rund, Nicole, Karasinsky, Anne, Adusumilli, Vijay S, Steinhauer, Christina, Scheibenstock, Sina, Händler, Kristian, Schultze, Joachim L, Calegari, Federico, Kempermann, Gerd
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441477/
https://www.ncbi.nlm.nih.gov/pubmed/34337766
http://dx.doi.org/10.15252/embj.2020107100
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author Zocher, Sara
Overall, Rupert W
Berdugo‐Vega, Gabriel
Rund, Nicole
Karasinsky, Anne
Adusumilli, Vijay S
Steinhauer, Christina
Scheibenstock, Sina
Händler, Kristian
Schultze, Joachim L
Calegari, Federico
Kempermann, Gerd
author_facet Zocher, Sara
Overall, Rupert W
Berdugo‐Vega, Gabriel
Rund, Nicole
Karasinsky, Anne
Adusumilli, Vijay S
Steinhauer, Christina
Scheibenstock, Sina
Händler, Kristian
Schultze, Joachim L
Calegari, Federico
Kempermann, Gerd
author_sort Zocher, Sara
collection PubMed
description Adult neurogenesis enables the life‐long addition of functional neurons to the hippocampus and is regulated by both cell‐intrinsic molecular programs and behavioral activity. De novo DNA methylation is crucial for embryonic brain development, but its role during adult hippocampal neurogenesis has remained unknown. Here, we show that de novo DNA methylation is critical for maturation and functional integration of adult‐born neurons in the mouse hippocampus. Bisulfite sequencing revealed that de novo DNA methyltransferases target neuronal enhancers and gene bodies during adult hippocampal neural stem cell differentiation, to establish neuronal methylomes and facilitate transcriptional up‐regulation of neuronal genes. Inducible deletion of both de novo DNA methyltransferases Dnmt3a and Dnmt3b in adult neural stem cells did not affect proliferation or fate specification, but specifically impaired dendritic outgrowth and synaptogenesis of newborn neurons, thereby hampering their functional maturation. Consequently, abolishing de novo DNA methylation modulated activation patterns in the hippocampal circuitry and caused specific deficits in hippocampus‐dependent learning and memory. Our results demonstrate that proper establishment of neuronal methylomes during adult neurogenesis is fundamental for hippocampal function.
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spelling pubmed-84414772021-09-27 De novo DNA methylation controls neuronal maturation during adult hippocampal neurogenesis Zocher, Sara Overall, Rupert W Berdugo‐Vega, Gabriel Rund, Nicole Karasinsky, Anne Adusumilli, Vijay S Steinhauer, Christina Scheibenstock, Sina Händler, Kristian Schultze, Joachim L Calegari, Federico Kempermann, Gerd EMBO J Articles Adult neurogenesis enables the life‐long addition of functional neurons to the hippocampus and is regulated by both cell‐intrinsic molecular programs and behavioral activity. De novo DNA methylation is crucial for embryonic brain development, but its role during adult hippocampal neurogenesis has remained unknown. Here, we show that de novo DNA methylation is critical for maturation and functional integration of adult‐born neurons in the mouse hippocampus. Bisulfite sequencing revealed that de novo DNA methyltransferases target neuronal enhancers and gene bodies during adult hippocampal neural stem cell differentiation, to establish neuronal methylomes and facilitate transcriptional up‐regulation of neuronal genes. Inducible deletion of both de novo DNA methyltransferases Dnmt3a and Dnmt3b in adult neural stem cells did not affect proliferation or fate specification, but specifically impaired dendritic outgrowth and synaptogenesis of newborn neurons, thereby hampering their functional maturation. Consequently, abolishing de novo DNA methylation modulated activation patterns in the hippocampal circuitry and caused specific deficits in hippocampus‐dependent learning and memory. Our results demonstrate that proper establishment of neuronal methylomes during adult neurogenesis is fundamental for hippocampal function. John Wiley and Sons Inc. 2021-08-02 2021-09-15 /pmc/articles/PMC8441477/ /pubmed/34337766 http://dx.doi.org/10.15252/embj.2020107100 Text en © 2021 The Authors. Published under the terms of the CC BY 4.0 license https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Zocher, Sara
Overall, Rupert W
Berdugo‐Vega, Gabriel
Rund, Nicole
Karasinsky, Anne
Adusumilli, Vijay S
Steinhauer, Christina
Scheibenstock, Sina
Händler, Kristian
Schultze, Joachim L
Calegari, Federico
Kempermann, Gerd
De novo DNA methylation controls neuronal maturation during adult hippocampal neurogenesis
title De novo DNA methylation controls neuronal maturation during adult hippocampal neurogenesis
title_full De novo DNA methylation controls neuronal maturation during adult hippocampal neurogenesis
title_fullStr De novo DNA methylation controls neuronal maturation during adult hippocampal neurogenesis
title_full_unstemmed De novo DNA methylation controls neuronal maturation during adult hippocampal neurogenesis
title_short De novo DNA methylation controls neuronal maturation during adult hippocampal neurogenesis
title_sort de novo dna methylation controls neuronal maturation during adult hippocampal neurogenesis
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441477/
https://www.ncbi.nlm.nih.gov/pubmed/34337766
http://dx.doi.org/10.15252/embj.2020107100
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