Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation and is altered with age

Sun Y. Maybury-Lewis, Abigail K. Brown, Mitchell Yeary, Anna Sloutskin, Shleshma Dhakal, Tamar Juven-Gershon, Ashley E. Webb

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Neural stem cells (NSCs) in the adult and aged brain are largely quiescent, and require transcriptional reprogramming to re-enter the cell cycle. However, the mechanisms underlying these changes and how they are altered with age remain undefined. Here, we identify the chromatin accessibility differences between primary neural stem/progenitor cells in quiescent and activated states. These distinct cellular states exhibit shared and unique chromatin profiles, both associated with gene regulation. Accessible chromatin states specific to activation or quiescence are active enhancers bound by key pro-neurogenic and quiescence factors. In contrast, shared sites are enriched for core promoter elements associated with translation and metabolism. Unexpectedly, through integrated analysis, we find that many sites that become accessible during NSC activation are linked to gene repression and associated with pro-quiescence factors, revealing a novel mechanism that may preserve quiescence re-entry. Furthermore, we report that in aged NSCs, chromatin regions associated with metabolic and transcriptional functions bound by key pro-quiescence transcription factors lose accessibility, suggesting a novel mechanism of age-associated NSC dysfunction. Together, our findings reveal how accessible chromatin states regulate the transcriptional switch between NSC quiescence and activation, and how this switch is affected with age.

Original languageEnglish
Article numbere13499
JournalAging Cell
Volume20
Issue number11
Early online date21 Oct 2021
DOIs
StatePublished - Nov 2021

Bibliographical note

Publisher Copyright:
© 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.

Funding

We thank members of the Webb laboratory for critical reading of the manuscript. This work was supported by NIH 5T32AG041688, Glenn/AFAR Scholarship for Research on the Biology of Aging, and Brown University Carney Institute Robin Chemers Neustein Graduate Research Award to S.M‐L., and NIH R01 AG053268 to A.E.W.

FundersFunder number
Brown University Carney Institute Robin Chemers NeusteinR01 AG053268
National Institutes of Health5T32AG041688
National Institute on AgingR01AG053268

    Keywords

    • aging
    • chromatin accessibility
    • neural stem cells
    • stem cell activation

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