TY - JOUR
T1 - Genome-wide RNA polymerase stalling shapes the transcriptome during aging
AU - Gyenis, Akos
AU - Chang, Jiang
AU - Demmers, Joris J.P.G.
AU - Bruens, Serena T.
AU - Barnhoorn, Sander
AU - Brandt, Renata M.C.
AU - Baar, Marjolein P.
AU - Raseta, Marko
AU - Derks, Kasper W.J.
AU - Hoeijmakers, Jan H.J.
AU - Pothof, Joris
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/2
Y1 - 2023/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85146569732&partnerID=8YFLogxK
U2 - 10.1038/s41588-022-01279-6
DO - 10.1038/s41588-022-01279-6
M3 - Article
C2 - 36658433
AN - SCOPUS:85146569732
SN - 1061-4036
VL - 55
SP - 268
EP - 279
JO - Nature genetics
JF - Nature genetics
IS - 2
ER -