FOXO3 shares common targets with ASCL1 genome-wide and inhibits ASCL1-dependent neurogenesis
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FOXO transcription factors are central regulators of longevity from worms to humans. FOXO3, the FOXO isoform associated with exceptional human longevity, preserves adult neural stem cell pools. Here, we identify FOXO3 direct targets genome-wide in primary cultures of adult neural progenitor cells (NPCs). Interestingly, FOXO3-bound sites are enriched for motifs for bHLH transcription factors, and FOXO3 shares common targets with the proneuronal bHLH transcription factor ASCL1/MASH1 in NPCs. Analysis of the chromatin landscape reveals that FOXO3 and ASCL1 are particularly enriched at the enhancers of genes involved in neurogenic pathways. Intriguingly, FOXO3 inhibits ASCL1-dependent neurogenesis in NPCs and direct neuronal conversion in fibroblasts. FOXO3 also restrains neurogenesis in vivo. Our study identifies a genome-wide interaction between the prolongevity transcription factor FOXO3 and the cell-fate determinant ASCL1 and raises the possibility that FOXO3's ability to restrain ASCL1-dependent neurogenesis may help preserve the neural stem cell pool.
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FOXO binds open chromatin, especially enhancers, and can act as a pioneer factor to open closed chromatin.
“Indeed, FOXO has been found to bind open chromatin, especially at enhancer regions (Eijkelenboom et al., 2013; Webb et al., 2013), and can act as a pioneer factor to open closed chromatin (Zaret and Carroll, 2011).”
From The Aging Epigenome (2016) · cites this paper as Webb et al., 2013
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- Authors
- Webb, A. E., Pollina, E. A., Vierbuchen, T., Urbán, N., Ucar, D., Leeman, D. S., Martynoga, B., Sewak, M., Rando, T. A., Guillemot, F., Wernig, M., & Brunet, A.
- Affiliations
- Stanford University (US)
- Institute for Stem Cell Biology and Regenerative Medicine (US)
- National Institute for Medical Research (GB)
- Corresponding author
- Brunet, Anne
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 4
- Issue
- 3
- Pages
- 477-491
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC3838667
- OpenAlex
- W2030484015
- Cited by
- 164
- References
- 62
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 10 · 2023: 6 · 2022: 10 · 2021: 13 · 2020: 11 · 2019: 23 · 2018: 13 · 2017: 24 · 2016: 11 · 2015: 12 · 2014: 17 · 2013: 3
- FWCI
- 6.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- National Science Foundation
- National Institutes of Health
- National Defense Science and Engineering Graduate
- National Institute on Aging (R37AG023806, F31AG043232, R01AG026648, P01AG036695)
- National Institute of Mental Health (R01MH092931)
- National Cancer Institute (T32CA009302)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- FOXO3, ASCL1, neurogenesis, neural progenitor cells, adult neural stem cells, bHLH transcription factors, direct transcriptional targets, neuronal conversion, fibroblasts, human longevity, cell fate determination
- MeSH terms
- Forkhead Box Protein O3, Animals, Binding Sites, Cell Differentiation, Genome, Cell Growth Processes, Mice, Forkhead Transcription Factors, Adult Stem Cells, Neurogenesis, Neural Stem Cells
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