Methylation deficiency disrupts biological rhythms from bacteria to humans

Area of Science:

• Metabolic pathways
• Circadian biology
• Evolutionary biology

Background:

• The methyl cycle is a fundamental metabolic pathway supplying methyl groups for crucial cellular processes like DNA and protein methylation.
• Previous research demonstrated that inhibiting the methyl cycle in mammals significantly disrupts circadian rhythms.
• The early evolutionary origins and widespread presence of both the methyl cycle and circadian clocks suggest a conserved link between them.

Purpose of the Study:

• To investigate the conserved nature of the relationship between the methyl cycle and biological rhythms across different life forms.
• To determine if methyl cycle inhibition affects circadian rhythms in a broad range of organisms.
• To explore potential mechanisms of resistance and therapeutic strategies related to methyl cycle function and circadian regulation.

Main Methods:

• Comparative analysis of methyl cycle inhibition effects on biological rhythms in various species, including unicellular algae, mammals, and cyanobacteria.
• Investigating the role of methylation in regulating circadian rhythms within cyanobacteria.
• Engineering mammalian cells to possess a bacteria-like methyl cycle for comparative studies.

Main Results:

• Methyl cycle inhibition was found to affect biological rhythms in species spanning over a billion years of evolution, from algae to humans.
• The cyanobacterial circadian clock exhibited resistance to methyl cycle inhibition.
• Methylations were confirmed to be regulators of circadian rhythms in cyanobacteria.
• Mammalian cells with a modified, bacteria-like methyl cycle demonstrated protection against methyl cycle inhibition-induced rhythm disruption.

Conclusions:

• The link between the methyl cycle and biological rhythms is conserved across a vast evolutionary timescale.
• Cyanobacteria possess a unique resistance to methyl cycle inhibition's effects on their clock.
• Rewiring the methyl cycle in mammalian cells offers a novel protective mechanism and suggests potential therapeutic avenues for methylation-related disorders.