Proximate Causes of Increased Transposon Expression with Age

In today's open access paper, researchers here look at some of the proximate causes of transposable element activation, the details of the epigenetic and transcriptional issues. It is well known that transposable element activity increases with age. These are sequences capable of self-replication in the genome, the remnants of ancient retroviral infections. Transposon activity is repressed in youth, the sequences hidden from transcription machinery within compact regions of the packaged genome, or hidden inside intron sequences that are normally excluded from transcription.

Aging produces a growing dysregulation of the epigenetic control of genomic structure and gene expression, allowing transposable elements to be exposed to transcription. Further, the process of splicing by which exons and introns are assembled into RNA molecules also becomes dysregulated, allowing occasional inclusion of introns that are normally excluded in youth. The resulting activation of transposable elements becomes a source of further damage and disarray. These sequences haphazardly insert copies of themselves into the genome, breaking existing genes. They can also potentially cause other harms via their gene products, such as via provoking forms of innate immune response to viral agents.

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

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 suggest 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.


Here is a large source of 'sterile inflammation'.

Transposable elements look like a virus to our cellular defenses.

Posted by: Lee at April 16th, 2024 4:42 AM

Transcriptomic markers of aging can be useful for studying age-related processes and diseases. However, noncoding repetitive element (RE) transcripts, which may play an important role in aging, are commonly overlooked in transcriptome studies-and their potential as a transcriptomic marker of aging has not been evaluated. Here, we used multiple RNA-seq datasets generated from human samples and Caenorhabditis elegans and found that most RE transcripts (a) accumulate progressively with aging; (b) can be used to accurately predict age; and (c) may be a good marker of biological age. The strong RE/aging correlations we observed are consistent with growing evidence that RE transcripts contribute directly to aging and disease.

Posted by: Lee at April 16th, 2024 5:07 AM
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