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bioRxiv · 10.1101/2021.10.11.463907

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

van Heesbeen, H. J.·von Oerthel, L.·de Vries, P. M.·Wagemans, M. R. J.·Smidt, M. P.
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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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van Heesbeen, H. J., von Oerthel, L., de Vries, P. M., Wagemans, M. R. J., Smidt, M. P.. 2021-10-12. Neuronal Dot1l is a broad mitochondrial gene-repressor associated with human brain aging via H3K79 hypermethylation. https://doi.org/10.1101/2021.10.11.463907

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