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Integrative epigenomic and transcriptomic analyses reveal metabolic switching by intermittent fasting in brain

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Abstract

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 (H3K9me3) 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 H3K9me3 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.

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Availability of data and material

High-throughput sequencing data have been submitted to the NCBI Sequence Read Archive (SRA) under accession number GSE135945.

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Not applicable.

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Acknowledgements

We thank Novogene (Beijing, China) for their kind assistance in data processing.

Funding

The Singapore National Medical Research Council Research Grants (Grant No. NMRC-CBRG-0102/2016 and NMRC-OFIRG-036/2017) supported this work. This study also supported by the National Research Foundation (NRF) funded by the Korean Government (Grant no. NRF-2019R1A2C3011422 and NRF-2019R1A5A2027340).

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Authors and Affiliations

  1. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Gavin Yong-Quan Ng, Sung Wook Kang, David Yang-Wei Fann, Joonki Kim, Manoor Prakash Hande, Karthik Mallilankaraman, Lina H. K. Lim, Brian K. Kennedy & Thiruma V. Arumugam

  2. Genome Institute of Singapore, Singapore, Singapore

    Dominic Paul Lee Kok Sheng & Roger Sik-Yin Foo

  3. School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea

    Han-Gyu Bae, Jinsu Park, Jeongmi Lee, Eunae Kim, Sunyoung Park, Jeung-Whan Han, Dong-Gyu Jo & Thiruma V. Arumugam

  4. Natural Products Research Center, Korea Institute of Science and Technology, Gangneung, Gangwon-do, Republic of Korea

    Joonki Kim

  5. Translational Biomedical Proteomics Group, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore

    Asfa Alli-Shaik & Jayantha Gunaratne

  6. Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Science Center, Amarillo, TX, USA

    Vardan Karamyan

  7. The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-IIan University, Ramat Gan, Israel

    Eitan Okun

  8. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Thameem Dheen & Jayantha Gunaratne

  9. Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA

    Raghu Vemuganti

  10. Department of Biochemistry, Yong Loo Lin School Medicine, National University of Singapore, Singapore, Singapore

    Brian K. Kennedy

  11. Buck Institute for Research On Aging, Novato, USA

    Brian K. Kennedy

  12. Centre for Cardiovascular Biology and Disease Research, Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, Australia

    Grant R. Drummond, Christopher G. Sobey & Thiruma V. Arumugam

  13. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Mark P. Mattson

  14. Centre for Translational Medicine, Cardiovascular Research Institute, National University Health Systems, National University of Singapore, Singapore, Singapore

    Roger Sik-Yin Foo

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  1. Gavin Yong-Quan Ng
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Contributions

G. Y. Q. N., R. S. Y. F., D. G. J., and T. V. A. conceived and designed the study. G. Y. Q. N., D. P. L. K. S., S. W. K., D. Y. W. F., J. K., and A. A. S. conducted animal experiments. G. Y. Q. N., D. P. L. K. S., S. W. K., H. B., J. P., J. L., E. K., S. P., J. W. H., and V. K. carried out the analyses and prepared the figures. G. Y. Q. N. and D. P. L. K. collected the sequencing data. E. O., T. D., M. P. H., R. V., K. M., L. H. K. L., and B. K. K. participated in the discussion of the project. G. R. D., C. G. S., J. G., and M. P. M. provided technical support to the project. G. Y. Q. N., R. S. Y. F., D. G. J., and T. V. A. drafted the manuscript. C. G. S., J. G., and M. P. M. edited the manuscript. R. S. Y. F., D. G. J., and T. V. A. supervised the analysis. The authors read and approved the final manuscript.

Corresponding authors

Correspondence to Roger Sik-Yin Foo, Dong-Gyu Jo or Thiruma V. Arumugam.

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All animal procedures were approved by the National University of Singapore Animal Care and Use Committee and performed according to the guidelines set forth by the National Advisory Committee for Laboratory Animal Research (NACLAR), Singapore. All aspects of the study were performed in accordance with the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines.

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Ng, G.YQ., Sheng, D.P.L.K., Bae, HG. et al. Integrative epigenomic and transcriptomic analyses reveal metabolic switching by intermittent fasting in brain. GeroScience 44, 2171–2194 (2022). https://doi.org/10.1007/s11357-022-00537-z

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