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

Autor: Occean JR; Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD, USA., Yang N; Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD, USA., Sun Y; Department of Biochemistry, Albert Einstein School of Medicine, Bronx, NY, USA., Dawkins MS; Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD, USA., Munk R; Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD, USA., Belair C; Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD, USA., Dar S; Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD, USA., Anerillas C; Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD, USA., Wang L; Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD, USA., Shi C; Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD, USA., Dunn C; Flow Cytometry Unit, National Institute on Aging, NIH, Baltimore, MD, USA., Bernier M; Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD, USA., Price NL; Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD, USA., Kim JS; Department of Biochemistry, Albert Einstein School of Medicine, Bronx, NY, USA., Cui CY; Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD, USA., Fan J; Computational Biology and Genomics Core, Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD, USA., Bhattacharyya M; Department of Pharmacology, Yale University, New Haven, CT, USA., De S; Computational Biology and Genomics Core, Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD, USA., Maragkakis M; Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD, USA., de Cabo R; Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD, USA., Sidoli S; Department of Biochemistry, Albert Einstein School of Medicine, Bronx, NY, USA., Sen P; Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD, USA. payel.sen@nih.gov.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jul 28; Vol. 15 (1), pp. 6357. Date of Electronic Publication: 2024 Jul 28.
DOI: 10.1038/s41467-024-50725-y
Abstrakt: 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.
(© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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