Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation and is altered with age
Open accessAbstract
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.
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Primary cultures of old quiescent NSCs exhibit increased chromatin accessibility at genes involved in quiescence, a potential mechanism underlying deep quiescence during ageing.
“Primary cultures of old quiescent NSCs also exhibit increased chromatin accessibility at genes involved in quiescence, a potential mechanism underlying deep quiescence during ageing98.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [98]
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Alvarez-Kuglen, M., Ninomiya, K., Qin, H., Rodriguez, D., Fiengo, L., Farhy, C., Hsu, W.-M., Kirk, B. D., Havas, A. P., Kaufman, C., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00685-1 · Cited by 17 · see citing works
Transcription factor networks in cellular quiescence
Mitra, M., Batista, S., & Coller, H. A. (2025) · Nature Cell Biology · doi:10.1038/s41556-024-01582-w · Cited by 16 · see citing works
“Furthermore, the WNT signalling pathway TF LEF1 co-regulates quiescence genes in NSCs with NFIX, a member of the nuclear factor I (NFI) family 61 .”
InfluentialPromoting Endogenous Neurogenesis as a Treatment for Alzheimer’s Disease
Zhang, Q., Liu, J., Chen, L., & Zhang, M. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-03145-2 · Cited by 14 · see citing works
The eroding chromatin landscape of aging stem cells
Shi, C., Wang, L., & Sen, P. (2020) · Translational Medicine of Aging · doi:10.1016/j.tma.2020.08.002 · Cited by 14 · see citing works
Peinado, P. J., & Urbach, A. (2023) · Cells · doi:10.3390/cells12162086 · Cited by 12 · see citing works
Age-dependent regenerative mechanisms in the brain
Vanacore, G., Christensen, J. B., & Bayin, N. S. (2024) · Biochemical Society Transactions · doi:10.1042/bst20230547 · Cited by 12 · see citing works
Li, Z.-X., & Han, J. J. (2024) · Translational Medicine of Aging · doi:10.1016/j.tma.2024.12.003 · Cited by 6 · see citing works
Murtaj, V., Butti, E., Martino, G., & Panina‐Bordignon, P. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1125785 · Cited by 8 · see citing works
“Enrichment analysis supports this notion, being stable chromatin associated with pathways regulating proliferation, translation, RNA polymerase II assembly, and metabolism, while dynamic chromatin was enriched for pathways associated with neuronal specification (Maybury-Lewis et al., 2021).”
BackgroundAge‐Associated Transcriptomic and Epigenetic Alterations in Mouse Hippocampus
Bilgic, M., Obata, R., Panfil, V., Zhu, Z., Saeki, M., Gotoh, Y., & Kishi, Y. (2025) · Aging Cell · doi:10.1111/acel.70233 · Cited by 5 · see citing works
“…cellular memory via the regulation of DNA, histone modifications, and chromatin structure, and its alteration during the aging process of many tissues is well known (Wang et al. 2022; Talens et al. 2012; Han and Brunet 2012; Maybury-Lewis et al. 2021; Ucar et al. 2017; Ernest Palomer et al. 2016).”
Neural stem cell quiescence is actively maintained by the epigenome
Malkowska, A., Ander, J., & Brand, A. H. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116732 · Cited by 3 · see citing works
“15 Finally, BMP-4-induced quiescence in mouse NSCs in vitro led to the activation of over 6,000 enhancers, twice as many as the number of active enhancers in proliferating NSCs, 64 indicating that it is likely that chromatin accessibility also increases in mammalian qNSCs. Chromatin accessibility…”
Hand2 represses non-cardiac cell fates through chromatin remodeling at cis- regulatory elementsPreprint
Komatsu, V., Cooper, B. H., Yim, P., Chan, K., Gong, W., Wheatley, L., Rohs, R., Fraser, S. E., & Trinh, L. A. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.09.23.559156 · Cited by 1 · see citing works
ImAge: an imaging approach to quantitate aging and rejuvenationPreprint
Alvarez-Kuglen, M., Rodriguez, D., Qin, H., Ninomiya, K., Fiengo, L., Farhy, C., Hsu, W.-M., Havas, A. P., Feng, G., Roberts, A. J., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.10.16.512441
Both intrinsic and microenvironmental factors contribute to the regulation of stem cell quiescence
Zhou, P., Hu, M., Li, Q., & Yang, G. (2024) · Journal of Cellular Physiology · doi:10.1002/jcp.31325
“…sequencing, chromatin immunoprecipitation with high ‐ throughput sequencing, and metabolomics, are also employed to decipher the regulation of stem cell dormancy (Chen et al., 2023; Llorens ‐ Bobadilla et al., 2015; Maybury ‐ Lewis et al., 2021; Shyh ‐ Chang & Ng, 2017; Srivastava et al., 2018).”
Kempermann, G. (2025) · Oxford University Press eBooks · doi:10.1093/med/9780197519233.003.0009
Scandella, V., Lykoskoufis, N. M. R., Soldati, H., Martino, L. D., Teav, T., Gallart‐Ayala, H., Ivanišević, J., Braun, S. M. G., & Knobloch, M. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.26.701741
Olaoye, O. J., Farrow, S. L., Cooper, A. A., Nyaga, D. M., & O'Sullivan, J. M. (2026) · BMC Medical Genomics · doi:10.1186/s12920-026-02375-w
“Our validated targets, ANKRD1 , CUZD1 , PRICKLE1 , RAB17 , are expressed in iPSCs, but magnitude and direction of effects may shift in differentiated lineages (e.g., cortical/dopaminergic neurons, smooth muscle) [67, 68].”
Metal homeostasis is remodeled in response to different quiescence triggersPreprint
Rakshit, A., Holtzen, S. E., Aron, A. T., Pezacki, A. T., Kahali, S., Das, S. K., Sanford, L., Ralle, M., Datta, A., & Palmer, A. E. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.05.21.727032
Akhtar, M. J., & Panwar, S. (2026) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2026.189663
Zhang, R., Liu, C., Zhou, Y., Zhao, K., Li, M., Cai, B., Wang, Y., Yuan, Z., Liu, Z., Yuan, Z., et al. (2026) · Advanced Science · doi:10.1002/advs.77547
- Authors
- Maybury‐Lewis, S. Y., Brown, A. K., Yeary, M., Sloutskin, A., Dhakal, S., Juven‐Gershon, T., & Webb, A. E.
- Affiliations
- Brown University (US)
- Bar-Ilan University (IL)
- Corresponding author
- Webb, Ashley E.
- ORCID
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2021-10-23
- Volume
- 20
- Issue
- 11
- Pages
- e13499-e13499
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC8590101
- OpenAlex
- W3205245111
- Cited by
- 27
- References
- 77
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 5 · 2023: 7 · 2022: 4 · 2021: 1 · 2020: 1
- FWCI
- 1.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Aging Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Office of Extramural Research, National Institutes of Health (AG053288)
- National Institute on Aging (5T32AG041688)
- American Federation for Aging Research (Scholarship for Research on the Biology of Aging)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- neural stem cells, chromatin accessibility, stem cell quiescence, stem cell activation, transcriptional reprogramming, aging, enhancers, core promoter, gene repression, neurogenesis, stem cell metabolism
- MeSH terms
- Chromatin Immunoprecipitation Sequencing, RNA-Seq, Aging, Animals, Brain, Cell Cycle, Cell Differentiation, Cells, Cultured, Chromatin, Gene Expression Regulation, Histones, Promoter Regions, Genetic, Transcriptional Activation, Cellular Senescence, Cell Proliferation, Mice, Gene Regulatory Networks, Neurogenesis, Neural Stem Cells
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