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Ageing-associated changes in transcription and splicing efficiency influence longevity

ABSTRACT: Ageing alters cellular homeostasis thereby compromising multiple cellular processes such as transcription and splicing. However, both the extent of these changes and the molecular mechanisms are not well understood so far. In order to address this question, we analyzed transcription-coupled processes on a genomic scale in five animal species (C. elegans, D. melanogaster, M. musculus, R. norvegicus, H. sapiens) at different adult life stages. Using total RNA profiling, we quantified alterations of transcriptional elongation speed, splicing efficiency, and splicing precision. We consistently observed across all analyzed species, that the genome-average speed of RNA polymerase II (Pol-II) increased with age. These effects were reverted under lifespan-extending conditions, such as dietary restriction or modulation of insulin signaling. Reducing the speed of Pol-II in worms and flies improved splicing efficiency and increased lifespan. We further observed reduced precision in nucleosome positioning in senescent compared to proliferating cells, which correlated with reduced splicing efficiency. Thus, an age-associated increase of transcriptional speed results in reduced splicing efficiency and splicing quality. These findings substantially extend our understanding about the molecular mechanisms driving animal aging, and suggest new mechanisms underlying lifespan-extending interventions.

ORGANISM(S): Caenorhabditis elegans Mus musculus Homo sapiens Drosophila melanogaster

PROVIDER: GSE102537 | GEO | 2023/01/26

REPOSITORIES: GEO

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Precise Maps of RNA Polymerase Reveal How Promoters Direct Initiation and Pausing

2013-02-01 | E-GEOD-42117 | biostudies-arrayexpress

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2010-12-09 | E-GEOD-25287 | biostudies-arrayexpress

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