Early‐onset aging and mitochondrial defects associated with loss of histone acetyltransferase 1 (Hat1)
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Histone acetyltransferase 1 (Hat1) is responsible for the acetylation of newly synthesized histone H4 on lysines 5 and 12 during the process of chromatin assembly. To understand the broader biological role of Hat1, we have generated a conditional mouse knockout model of this enzyme. We previously reported that Hat1 is required for viability and important for mammalian development and genome stability. In this study, we show that haploinsufficiency of Hat1 results in a significant decrease in lifespan. Defects observed in Hat1+/− mice are consistent with an early‐onset aging phenotype. These include lordokyphosis (hunchback), muscle atrophy, minor growth retardation, reduced subcutaneous fat, cancer, and paralysis. In addition, the expression of Hat1 is linked to the normal aging process as Hat1 mRNA and protein becomes undetectable in many tissues in old mice. At the cellular level, fibroblasts from Hat1 haploinsufficient embryos undergo early senescence and accumulate high levels of p21. Hat1+/− mouse embryonic fibroblasts (MEFs) display modest increases in endogenous DNA damage but have significantly higher levels of reactive oxygen species (ROS). Consistently, further studies show that Hat1−/− MEFs exhibit mitochondrial defects suggesting a critical role for Hat1 in mitochondrial function. Taken together, these data show that loss of Hat1 induces multiple hallmarks of early‐onset aging.
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HAT1 is a cytoplasmic histone deacetylase whose loss is associated with early onset ageing and mitochondrial defects, and whose expression is reduced under treatment with hypoxic agents.
“HAT1 (FC = −1.12, p = 0.05) is a cytoplasmic histone deacetylase, for which loss is associated with early onset ageing and mitochondrial defects [105], and for which expression is reduced under treatment with hypoxic agents [159].”
From Early onset senescence and cognitive impairment in a murine model of repeated mTBI (2021) · cites this paper as [105]
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The flip side of sirtuins: the emerging roles of protein acetyltransferases in aging
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Self-citationProteomics and machine learning in the prediction and explanation of low pectoralis muscle area
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Self-citationHistone Acetylation Landscape and the Role of HAT1 in Regulating Corneal Epithelial Wound Healing
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Epigenetic regulation of nuclear mechanics
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Histone acetyltransferase HAT1 regulates intestinal stem cell proliferation and differentiation
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Self-citationLinking mitochondrial dysfunction to sarcopenia
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HAT1 participates in spermatogenesis of Eriocheir sinensis by regulating chromatin aggregationPreprint
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HAT1 Regulates Intestinal Stem Cell Proliferation and DifferentiationPreprint
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Self-citationHat1 Orchestrates Heterochromatin Structure by Regulating Localization of H3K9 Methyltransferases
Martin, C. J., Popova, L. V., Nagarajan, P., Oser, E. A., Lovejoy, C. M., Sunkel, B. D., Stanton, B. Z., Freitas, M. A., & Parthun, M. R. (2026) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2026.113659
Self-citation
- Authors
- Nagarajan, P., Agudelo Garcia, P. A., Iyer, C. C., Popova, L. V., Arnold, W. D., & Parthun, M. R.
- Affiliations
- The Ohio State University (US)
- Department of Biological Chemistry and Pharmacology, The Ohio State University Columbus Ohio
- Corresponding author
- Parthun, Mark R.
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2019-07-10
- Volume
- 18
- Issue
- 5
- Pages
- e12992-e12992
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC6718594
- OpenAlex
- W2961798823
- Cited by
- 43
- References
- 67
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 9 · 2023: 7 · 2022: 3 · 2021: 8 · 2020: 4
- FWCI
- 1.36
- 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
- National Institutes of Health (GM062970)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- HAT1, haploinsufficiency, lifespan reduction, histone H4 acetylation, chromatin assembly, mitochondrial defects, cellular senescence, p21, reactive oxygen species, DNA damage, mouse knockout models, muscle atrophy
- MeSH terms
- Aging, Animals, Mice, Inbred C57BL, Mitochondria, Mice, Knockout, Mice, Histone Acetyltransferases
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