Histone H4 lysine 16 acetylation regulates cellular lifespan
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Cells undergoing developmental processes are characterized by persistent non-genetic alterations in chromatin, termed epigenetic changes, represented by distinct patterns of DNA methylation and histone post-translational modifications. Sirtuins, a group of conserved NAD(+)-dependent deacetylases or ADP-ribosyltransferases, promote longevity in diverse organisms; however, their molecular mechanisms in ageing regulation remain poorly understood. Yeast Sir2, the first member of the family to be found, establishes and maintains chromatin silencing by removing histone H4 lysine 16 acetylation and bringing in other silencing proteins. Here we report an age-associated decrease in Sir2 protein abundance accompanied by an increase in H4 lysine 16 acetylation and loss of histones at specific subtelomeric regions in replicatively old yeast cells, which results in compromised transcriptional silencing at these loci. Antagonizing activities of Sir2 and Sas2, a histone acetyltransferase, regulate the replicative lifespan through histone H4 lysine 16 at subtelomeric regions. This pathway, distinct from existing ageing models for yeast, may represent an evolutionarily conserved function of sirtuins in regulation of replicative ageing by maintenance of intact telomeric chromatin.
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Overexpression of SIR2 or histones, or deletion of SET2, extends yeast lifespan, indicating epigenetic changes are a cause, not merely a biomarker, of yeast aging.
“Overexpression of SIR2, histones, or deletion of the histone methyltransferase gene SET2, extends yeast lifespan, indicating that epigenetic changes are not merely a biomarker, but a cause of yeast aging (Dang et al., 2009; Feser et al., 2010; Hu et al., 2014; Kaeberlein et al., 1999; Ryu et al., 2014).”
From Loss of epigenetic information as a cause of mammalian aging (2023) · cites this paper as Dang et al., 2009
The section ‘Sas2 has opposing effects on H4K16ac and lifespan’ (page not supplied) reports that SIR2 overexpression extends yeast lifespan. The Discussion (page not supplied) links histone acetylation and telomeric chromatin to longevity, supporting the point that epigenetic changes can affect aging. This paper does not establish lifespan extension from histone overexpression or SET2 deletion; it reports lifespan extension from SAS2 deletion instead. (LLM, conf=0.88)
Experimental — accuracy not yet measuredReduced H3K122ac extends lifespan of budding yeast, and H3K27ac and H3K56ac decrease in many human immune cell types.
“Reduced levels of H3K122ac extend the lifespan of budding yeast (Sen et al., 2015) and levels of H3K27ac and H3K56ac decrease in many human immune cell types (Cheung et al., 2018; Dang et al., 2009).”
From Loss of epigenetic information as a cause of mammalian aging (2023) · cites this paper as Dang et al., 2009
The “Histone modifications change in old cells” section (page unavailable) reports that H3K56ac decreased with age in yeast mother cells. It does not establish a decrease in H3K56ac or H3K27ac across human immune cell types. The H3K122ac lifespan claim is attached to Sen et al., not to Dang et al. (LLM, conf=0.87)
Experimental — accuracy not yet measuredOlder yeast have less active Sir2 and increased H4K16 acetylation at telomeres.
“Consistent with a link between longevity and telomere silencing, older yeast have less active Sir2 (a sirtuin) and, as a result, increased H4K16 acetylation at telomeres (Dang et al., 2009).”
From The Aging Epigenome (2016) · cites this paper as Dang et al., 2009
The same changes documented in ageing cells, such as demethylation of retrotransposons and satellite DNA and high levels of their transcription, are also observed in human cancer.
“Of note, the same changes documented in ageing cells, such as demethylation of retrotransposons and satellite DNA and high levels of their transcription, are also observed in human cancer 73-75 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [75]
Demethylation of retrotransposons and satellites and high levels of their transcription are observed in ageing cells and in human cancer.
“Demethylation of retrotransposons and satellites and high levels of their transcription are observed in ageing cells 47 and in human cancer 73-75 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [75]
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Self-citation
- Authors
- Dang, W., Steffen, K. K., Perry, R., Dorsey, J. A., Johnson, F. B., Shilatifard, A., Kaeberlein, M., Kennedy, B. K., & Berger, S. L.
- Affiliations
- The Wistar Institute (US)
- University of Pennsylvania (US)
- Stowers Institute for Medical Research (US)
- University of Washington (US)
- Corresponding author
- Berger, Shelley L.
- ORCID
- Venue
- Nature
- Published
- 2009-06
- Volume
- 459
- Issue
- 7248
- Pages
- 802-807
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2702157
- OpenAlex
- W2017117976
- Cited by
- 667
- References
- 46
- Citations by year
- 2026: 18 · 2025: 29 · 2024: 28 · 2023: 25 · 2022: 31 · 2021: 69 · 2020: 34 · 2019: 36 · 2018: 37 · 2017: 41 · 2016: 42 · 2015: 41 · 2014: 33 · 2013: 50 · 2012: 49
- FWCI
- 36.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (R01AG025549)
- National Cancer Institute (R01CA089455)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- H4K16ac, Sir2, sirtuins, replicative lifespan, aging, subtelomeric regions, telomeric chromatin, transcriptional silencing, histone acetyltransferase, chromatin silencing, Saccharomyces cerevisiae, NAD+-dependent deacetylase
- MeSH terms
- Acetylation, Acetyltransferases, Cell Division, Chromatin, Epistasis, Genetic, Histone Deacetylases, Histones, Lysine, Mutation, Saccharomyces cerevisiae, Transcription, Genetic, Gene Expression Regulation, Fungal, Telomere, Gene Silencing, Saccharomyces cerevisiae Proteins, Sirtuins, Silent Information Regulator Proteins, Saccharomyces cerevisiae, Mutant Proteins, Histone Acetyltransferases, Sirtuin 2, Histone Deacetylase Inhibitors
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