A concerted increase in readthrough and intron retention drives transposon expression during aging and senescence

Abstract

Aging and senescence are characterized by pervasive transcriptional dysfunction, including increased expression of transposons and introns. Our aim was to elucidate mechanisms behind this increased expression. Most transposons are found within genes and introns, with a large minority being close to genes. This raises the possibility that transcriptional readthrough and intron retention are responsible for age-related changes in transposon expression rather than expression of autonomous transposons. To test this, we compiled public RNA-seq datasets from aged human fibroblasts, replicative and drug-induced senescence in human cells and RNA-seq from aging mice and senescent mouse cells. Indeed, our reanalysis revealed a correlation between transposons expression, intron retention and transcriptional readthrough across samples and within samples. Both intron retention and readthrough increased with aging or cellular senescence and these transcriptional defects were more pronounced in human samples as compared to those of mice. In support of a causal connection between readthrough and transposon expression, analysis of models showing induced transcriptional readthrough confirmed that they also show elevated transposon expression. Taken together, our data shows that elevated transposon reads during aging seen in various RNA-seq dataset are concomitant with multiple transcriptional defects. Intron retention and transcriptional readthrough are the most likely explanation for the expression of transposable elements that lack a functional promoter.

Transposon-triggered epigenetic chromatin dynamics modulate EFR-related pathogen response

“…The specific distribution of NET-seq reads suggested that Pol II-dependent Ea-IR -transcripts contain also XI-k mRNA sequences (Figure 5A). In animals, specific stressful conditions can trigger Pol II to read through termination sites, producing transcripts that include sequences from nearby transposons 51-53 . Similarly, we observed Pol II readthrough at the termination sites of XI-k , leading to the incorporation of Ea-IR sequences into Xl-k transcripts (Figure 5A).…”

Xrp1 governs the stress response program to spliceosome dysfunction

“…Interestingly, excessive TE activation has been observed in senescent human cells and in response to aging in both Drosophila and mammals ( 101–104 ). Moreover, a recent analysis of RNA-seq datasets of senescent or aged cells in both humans and mice correlated increased transposon expression with transcriptional readthrough and intron retention ( 105 ).…”