Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging

Occean, J. R.; Yang, N.; Sun, Y.; Dawkins, M. S.; Munk, R.; Belair, C.; Dar, S.; Anerillas, C.; Wang, L.; Shi, C.; Dunn, C.; Bernier, M.; Price, N. L.; Kim, J. S.; Cui, C.-Y.; Fan, J.; Bhattacharyya, M.; De, S.; Maragkakis, M.; Cabo, R. d.; Sidoli, S.; Sen, P.

doi:10.1101/2023.02.15.528714

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bioRxiv · 10.1101/2023.02.15.528714

Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging

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Abstract

DNA hydroxymethylation (5hmC), the most abundant oxidative derivative of DNA methylation, is typically enriched at enhancers and gene bodies of transcriptionally active and tissue-specific genes. Although aberrant genomic 5hmC has been implicated in age-related diseases, its functional role in aging remains unknown. Here, using mouse liver and cerebellum as model organs, we show that 5hmC accumulates in gene bodies associated with tissue-specific function and restricts the magnitude of gene expression changes with age. Mechanistically, 5hmC decreases the binding of splicing associated factors and correlates with age-related alternative splicing events. We found that various age-related contexts, such as prolonged quiescence and senescence, drive the accumulation of 5hmC with age. We provide evidence that this age-related transcriptionally restrictive function is conserved in mouse and human tissues. Our findings reveal that 5hmC regulates tissue-specific function and may play a role in longevity.

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Occean, J. R., Yang, N., Sun, Y., Dawkins, M. S., Munk, R., Belair, C., Dar, S., Anerillas, C., Wang, L., Shi, C., Dunn, C., Bernier, M., Price, N. L., Kim, J. S., Cui, C.-Y., Fan, J., Bhattacharyya, M., De, S., Maragkakis, M., Cabo, R. d., Sidoli, S., Sen, P.. 2023-02-15. Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging. https://doi.org/10.1101/2023.02.15.528714

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