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PreprintCited by 12Epigenetics and DNA MethylationGenetics, Aging, and Longevity in Model OrganismsCancer-related gene regulation

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Neuronal Dot1l is a broad mitochondrial gene-repressor associated with human brain aging via H3K79 hypermethylation

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Van Heesbeen, H.J, Von Oerthel, L, De Vries, P.M, Wagemans, M.R.J, Smidt, M.P.·2021·International Journal of Molecular Sciences
DOI 10.1101/2021.10.11.463907PMC PMC9862808

Preprint — published as 10.3390/ijms24021387 · Paper page

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Abstract

Methylation of histone 3 at lysine 79 (H3K79) and its catalyst, disrupter of telomeric silencing (Dot1l), have been coupled to multiple forms of stress like bioenergetic and ER challenges. However, studies on H3K79 methylation and Dot1l in the aging brain and neurons are very limited. This together with increasing evidence of a dynamic neuroepigenome made us wonder if H3K79 methylation and Dot1l could play unknown roles in brain aging and associated disorders. In aged humans, we found strong and consistent hypermethylation of H3K79 in neurons that accumulate lipofuscine, while neuronal Dot1l transcript abundance reacts to bioenergenic and oxidative challenges. Indeed, in dopaminergic neurons we found rapid global H3K79me turnover (<12h). While shortly after reduction of H3K79 methylation, synaptic transcripts decreased while mitochondrial genes, particularly respiratory chain transcripts increased. Strikingly, 6 months after reduction of Dot1l levels, almost solely a variety of mitochondrial genes linked to aging and Parkinsons disease remained increased. These profiles are in much detail inverse to those described in hallmark PD and aging studies and associate Dot1l and H3K79me with neuronal stress in the aging brain while putting Dot1l forward as dynamic master regulator of mitochondrial transcription in dopamine neurons.

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Metadata

Authors
Van Heesbeen, H. J., Von Oerthel, L., De Vries, P. M., Wagemans, M. R. J., & Smidt, M. P.
Affiliations
University of Amsterdam (NL)
Corresponding author
  • Van Heesbeen, H.J
  • Smidt, M.P.
ORCID
Venue
International Journal of Molecular Sciences
Publisher
openRxiv
Published
2021-10-12
Volume
24
Issue
2
Pages
1387-1387
ISSN
1422-0067 (ISSN-L)
DOI
10.1101/2021.10.11.463907
PMC
PMC9862808
OpenAlex
W4315649336
Cited by
12
References
1
Citations by year
2026: 4 · 2025: 3 · 2024: 2 · 2023: 3
FWCI
1.07
Type
journal article
Language
en
Open access
Licence
cc-by
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 (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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