Neuronal Dot1l Activity Acts as a Mitochondrial Gene-Repressor Associated with Human Brain Aging via H3K79 Hypermethylation
Open accessPublished version of a preprint
Abstract
Methylation of histone 3 at lysine 79 (H3K79) and its catalyst, a disrupter of telomeric silencing (DOT1l), have been coupled to multiple forms of stress, such as bioenergetic and ER challenges. However, studies on H3K79 methylation and Dot1l in the (aging) brain and neurons are limited. This, together with the increasing evidence of a dynamic neuroepigenome, made us wonder if H3K79 methylation and its activator Dot1l could play important roles in brain aging and associated disorders. In aged humans, we found strong and consistent global hypermethylation of H3K79 in neurons. Specific in dopaminergic neurons, we found a strong increase in H3K79 methylation in lipofucsin positive neurons, which are linked to pathology. In animals, where we conditionally removed Dot1l, we found a rapid loss of H3K79 methylation. As a consequence, we found some decrease in specific dopaminergic genes, and surprisingly, a clear up-regulation of almost all genes belonging to the family of the respiratory chain. These data, in relation to the observed increase in global H3K79 methylation, suggest that there is an inverse relationship between H3K79 methylation and the capacity of energy metabolism in neuronal systems.
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Cites
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- Authors
- Van Heesbeen, H. J., Von Oerthel, L., De Vries, P. M., Wagemans, C. M. R. J., & Smidt, M. P.
- Affiliations
- Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, Room C4.102, 1098 XH Amsterdam, The Netherlands
- University of Amsterdam (NL)
- Corresponding author
- Smidt, Marten P.
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2023-01-10
- Volume
- 24
- Issue
- 2
- Pages
- 1387
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC9862808
- OpenAlex
- W4315649336
- Cited by
- 12
- References
- 7
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 2 · 2023: 3
- FWCI
- 1.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UvA-DARE (University of Amsterdam) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek-Aard en Levenswetenschappen (865.09.002)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Keywords
- DOT1L, H3K79 methylation, brain aging, dopaminergic neurons, mitochondrial gene expression, neuronal energy metabolism, histone methylation, neuroepigenetics
- MeSH terms
- Aged, Animals, Brain, Histones, Humans, Methyltransferases, Neurons, Histone-Lysine N-Methyltransferase, DNA Methylation, Genes, Mitochondrial
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