Methylation deficiency disrupts biological rhythms from bacteria to humans

Abstract

The methyl cycle is a universal metabolic pathway providing methyl groups for the methylation of nuclei acids and proteins, regulating all aspects of cellular physiology. We have previously shown that methyl cycle inhibition in mammals strongly affects circadian rhythms. Since the methyl cycle and circadian clocks have evolved early during evolution and operate in organisms across the tree of life, we sought to determine whether the link between the two is also conserved. Here, we show that methyl cycle inhibition affects biological rhythms in species ranging from unicellular algae to humans, separated by more than 1 billion years of evolution. In contrast, the cyanobacterial clock is resistant to methyl cycle inhibition, although we demonstrate that methylations themselves regulate circadian rhythms in this organism. Mammalian cells with a rewired bacteria-like methyl cycle are protected, like cyanobacteria, from methyl cycle inhibition, providing interesting new possibilities for the treatment of methylation deficiencies.

m6A RNA Methylation in Marine Plants: First Insights and Relevance for Biological Rhythms

“…In the seagrass Posidonia oceanica , such physiological rhythms have been correlated with the expression patterns of related genes (e.g., photosynthesis and respiratory genes), which seem to be responsible for driving such changes throughout the day [ 54 ]. However, their upstream regulatory mechanisms, which could involve epigenetic and/or epitranscriptomic mechanisms [ 39 , 40 , 41 , 42 ], remain unknown.…”

“…Recent studies have shown that epigenetic and epitranscriptomic regulations affect the expression of clock components in several organisms [ 28 , 40 , 41 ], but only few studies have been conducted on the epigenetic and post-transcriptional controls of circadian clock functions in plants [ 42 , 43 , 44 , 45 ] and almost none on the role of RNA methylation (m 6 A) in regulating clock-related genes [ 46 , 47 ]. In mammals, it has been demonstrated that a large number of transcripts encoding core clock components, as well as clock output genes, are enriched in m 6 A methylation sites [ 40 , 48 ] and that changes in their m 6 A levels can affect circadian rhythms, cellular growth, and ultimately survival [ 49 ].…”

Functional and Pathological Roles of AHCY

“…In mouse embryonic fibroblasts, this m6A reduction upon AHCY inhibition is functionally linked to a delay in processing RNAs from circadian rhythm genes, thus impacting their oscillatory behavior response (Fustin et al, 2013). Extending this observation, Fustin et al (2020) have recently found that targeting AHCY activity with 3-deazaneplanocin A (DZnep) produces a loss in the oscillatory transcriptional response of circadian-associated genes in different organisms (from unicellular algae to humans). The loss of the oscillatory transcriptional activation of the Hes7 gene during somitogenesis on DZnep-treated mouse embryos suggests that methylation flux, directed by AHCY, is a universal regulator of biological circadian rhythms in metazoans (Fustin et al, 2020).…”

Differential effects of environmental and endogenous 24h rhythms within a deep-coverage spatiotemporal proteome

“…To reduce sample complexity, we employed the uniquely minimal cellular and genomic complexity of the model cell Ostreococcus tauri , a picoeukaryotic alga. This cell type is well established as a cellular model for circadian rhythms across eukaryotes 6, 9, 19 , and is highly amenable to culture under natural diurnal versus constant circadian conditions. Our results provide a rare insight into the complex relationship between environmental and circadian regulation of protein abundance across time, revealing a strikingly differential spatiotemporal proteome under these two conditions.…”