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

Author

Listed:
  • James R. Occean

    (NIH)

  • Na Yang

    (NIH)

  • Yan Sun

    (Albert Einstein School of Medicine)

  • Marshall S. Dawkins

    (NIH)

  • Rachel Munk

    (NIH)

  • Cedric Belair

    (NIH)

  • Showkat Dar

    (NIH)

  • Carlos Anerillas

    (NIH)

  • Lin Wang

    (NIH)

  • Changyou Shi

    (NIH)

  • Christopher Dunn

    (NIH)

  • Michel Bernier

    (NIH)

  • Nathan L. Price

    (NIH)

  • Julie S. Kim

    (Albert Einstein School of Medicine)

  • Chang-Yi Cui

    (NIH)

  • Jinshui Fan

    (NIH)

  • Moitrayee Bhattacharyya

    (Yale University)

  • Supriyo De

    (NIH)

  • Manolis Maragkakis

    (NIH)

  • Rafael Cabo

    (NIH)

  • Simone Sidoli

    (Albert Einstein School of Medicine)

  • Payel Sen

    (NIH)

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.

Suggested Citation

  • James R. Occean & Na Yang & Yan Sun & Marshall S. Dawkins & Rachel Munk & Cedric Belair & Showkat Dar & Carlos Anerillas & Lin Wang & Changyou Shi & Christopher Dunn & Michel Bernier & Nathan L. Price, 2024. "Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50725-y
    DOI: 10.1038/s41467-024-50725-y
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