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

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...

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Veröffentlicht in:Nature communications Jg. 15; H. 1; S. 6357 - 22
Hauptverfasser: Occean, James R., Yang, Na, Sun, Yan, Dawkins, Marshall S., Munk, Rachel, Belair, Cedric, Dar, Showkat, Anerillas, Carlos, Wang, Lin, Shi, Changyou, Dunn, Christopher, Bernier, Michel, Price, Nathan L., Kim, Julie S., Cui, Chang-Yi, Fan, Jinshui, Bhattacharyya, Moitrayee, De, Supriyo, Maragkakis, Manolis, de Cabo, Rafael, Sidoli, Simone, Sen, Payel
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 28.07.2024
Nature Publishing Group
Nature Portfolio
Schlagworte:
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5-Methylcytosine - analogs & derivatives
5-Methylcytosine - metabolism
631/208/177
631/337/100
64/60
82/58
Age
Age related diseases
Aging
Aging - genetics
Aging - metabolism
Alternative Splicing
Animals
Bioaccumulation
Cerebellum
Cerebellum - metabolism
Deoxyribonucleic acid
DNA
DNA Methylation
Enhancers
Female
Gene expression
Gene Expression Regulation
Human tissues
Humanities and Social Sciences
Humans
Liver - metabolism
Liver diseases
Longevity - genetics
Male
Mice
Mice, Inbred C57BL
multidisciplinary
Science
Science (multidisciplinary)
Senescence
Transcription, Genetic
ISSN:2041-1723, 2041-1723
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Zusammenfassung: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. DNA hydroxymethylation (5hmC) is typically altered in age-related diseases. Here, the authors show that 5hmC accumulates in gene bodies, partially due to prolonged quiescence, and restricts the magnitude of transcriptional changes with age.
Bibliographie:ObjectType-Article-1
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ObjectType-Feature-2
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-50725-y