Genome-wide RNA polymerase stalling shapes the transcriptome during aging

Akos Gyenis, Jiang Chang, Joris J.P.G. Demmers, Serena T. Bruens, Sander Barnhoorn, Renata M.C. Brandt, Marjolein P. Baar, Marko Raseta, Kasper W.J. Derks, Jan H.J. Hoeijmakers, Joris Pothof*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

35 Citations (Scopus)
23 Downloads (Pure)

Abstract

Gene expression profiling has identified numerous processes altered in aging, but how these changes arise is largely unknown. Here we combined nascent RNA sequencing and RNA polymerase II chromatin immunoprecipitation followed by sequencing to elucidate the underlying mechanisms triggering gene expression changes in wild-type aged mice. We found that in 2-year-old liver, 40% of elongating RNA polymerases are stalled, lowering productive transcription and skewing transcriptional output in a gene-length-dependent fashion. We demonstrate that this transcriptional stress is caused by endogenous DNA damage and explains the majority of gene expression changes in aging in most mainly postmitotic organs, specifically affecting aging hallmark pathways such as nutrient sensing, autophagy, proteostasis, energy metabolism, immune function and cellular stress resilience. Age-related transcriptional stress is evolutionary conserved from nematodes to humans. Thus, accumulation of stochastic endogenous DNA damage during aging deteriorates basal transcription, which establishes the age-related transcriptome and causes dysfunction of key aging hallmark pathways, disclosing how DNA damage functionally underlies major aspects of normal aging.

Original languageEnglish
Pages (from-to)268-279
Number of pages12
JournalNature Genetics
Volume55
Issue number2
DOIs
Publication statusPublished - Feb 2023

Bibliographical note

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© 2023, The Author(s).

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