Neuronal Dot1l Activity Acts as a Mitochondrial Gene-Repressor Associated with Human Brain Aging via H3K79 Hypermethylation

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.

Male-specific behavioral and transcriptomic changes in aging C. elegans neurons

“…In mammals the H3K79 methyltransferase DOTL1 mediates neurogenesis and neuronal energy metabolism. 66 , 67 DOT1L in C. elegans has been shown to regulate H3K9me2 in enhancer regions and regulate RNAi efficiency through suppression of heterochromatin, thus eliciting a global impact on gene expression. 56 , 57 Interestingly, in mammals, histone modification enzymes are also among the X chromosomal inactivation (XCI) escapee genes that are found to be expressed from the inactivated X chromosome.…”

Male-specific features ofC. elegansneuronal aging

“…We then examined individual genes with a hermaphroditic bias on the X chromosome, and found that the genes more highly expressed in hermaphrodites in aged neurons are enriched in H3K79 histone modification, in addition to neuronal signaling genes. In mammals the H3K79 methyltransferase DOTL1 mediates neurogenesis and neuronal energy metabolism (Appiah et al, 2023; Van Heesbeen et al, 2023). DOT1L in C. elegans has been shown to regulate H3K9me2 in enhancer regions and regulate RNAi efficiency through suppression of heterochromatin, thus eliciting a global impact on gene expression (Esse et al, 2019; Esse and Grishok, 2020).…”