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Intermittent fasting (IF) remains the most effective intervention to achieve robust anti-aging effects and attenuation of age-related diseases in various species. Epigenetic modifications mediate the biological effects of several environmental factors on gene expression; however, no information is available on the effects of IF on the epigenome. Here, we first found that IF for 3 months caused modulation of H3K9 trimethylation (H3K9me(3)) in the cerebellum, which in turn orchestrated a plethora of transcriptomic changes involved in robust metabolic switching processes commonly observed during IF. Second, a portion of both the epigenomic and transcriptomic modulations induced by IF was remarkably preserved for at least 3 months post-IF refeeding, indicating that memory of IF-induced epigenetic changes was maintained. Notably, though, we found that termination of IF resulted in a loss of H3K9me(3) regulation of the transcriptome. Collectively, our study characterizes the novel effects of IF on the epigenetic-transcriptomic axis, which controls myriad metabolic processes. The comprehensive analyses undertaken in this study reveal a molecular framework for understanding how IF impacts the metabolo-epigenetic axis of the brain and will serve as a valuable resource for future research. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-022-00537-z.

Intermittent fasting (IF) is a lifestyle intervention comprising a dietary regimen in which energy intake is restricted via alternating periods of fasting and ad libitum food consumption, without compromising nutritional composition. While epigenetic modifications can mediate effects of environmental factors on gene expression, no information is yet available on potential effects of IF on the epigenome. In this study, we found that IF causes modulation of histone H3 lysine 9 trimethylation (H3K9me3) epigenetic mark in the cerebellum of male C57/BL6 mice, which in turn orchestrates a plethora of transcriptomic changes involved in the robust metabolic switching processes commonly observed during IF. Interestingly, both epigenomic and transcriptomic modulation continued to be observed after refeeding, suggesting that memory of the IF-induced epigenetic change is maintained at the locus. Notably though, we found that termination of IF results in a loss of H3K9me3 regulation of the transcriptome. Collectively, our study characterizes a novel mechanism of IF in the epigenetic-transcriptomic axis, which controls myriad metabolic process changes. In addition to providing a valuable and innovative resource, our systemic analyses reveal molecular framework for understanding how IF impacts the metaboloepigenetics axis of the brain.Highlights○ Intermittent fasting (IF) and refeeding modifies epigenome in the cerebellum○ Integrative epigenomic and transcriptomic analyses revealed metabolic switching○ IF affects the metaboloepigenetics axis in regulating metabolic processes○ Integrative analyses revealed a loss of epigenetic reprogramme following refeeding