The role of retrotransposable elements in ageing and age-associated diseases

Gorbunova, Vera; Seluanov, Andrei; Mita, Paolo; McKerrow, Wilson; Fenyö, David; Boeke, Jef D.; Linker, Sara B.; Gage, Fred H.; Kreiling, Jill A.; Petrashen, Anna P.; Woodham, Trenton A.; Taylor, Jeanette; Helfand, Stephen L.; Sedivy, John M.

doi:10.1038/s41586-021-03542-y

Cited by 202 publications

(187 citation statements)

References 154 publications

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“…It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted September 28, 2021. ; https://doi.org/10.1101/2021.09.27.461867 doi: bioRxiv preprint had a lower DI and no intact LINE ORFs were found in R. aegyptiacus and P. vampyrus which had the lowest DI among the considered chiropteran species. Previous works hypothesised that bats have a higher tolerance for the activity of transposable elements with alternative ways to dampen health or problematics to these species [41,53]. Given our observation about the common drop of non-LTR retrotransposon accumulation in long-lived bats and H. glaber, we add to the previous hypothesis that it is the particular repression of the activity of non-LTR retrotransposon that confers resistance to cancer.…”

Section: Discussionmentioning

confidence: 54%

“…An increasing number of studies are finding a link between TEs, ageing, and pathologies. As discussed in previous studies [39,41] it is reasonable that genome instability derived by certain TEs could facilitate age-associated pathologies. The involvement of non-LTR retrotransposons in processes as the inflammation pathway explain the tight symbiosis between these mobile elements and the host genome, for this reason we think that in the long term they could accidentally act as promoting factor, more than as simple biomarker, in cancer evolution and other age-associated conditions.…”

Section: Discussionmentioning

confidence: 81%

“…To deepen the understanding of the relationship between TEs and longevity, we chose to perform a comparative genomic analysis of TE elements among mammalian species with different lifespans. TEs that are most likely to cause mutations and genomic instability are the ones currently active, i.e., able to move throughout the genome [38][39][40][41]. Since there are no transposition essays available for many organisms, we use the genetic divergence of the TE insertions from their consensus sequences as a proxy for their active/inactive state [12].…”

Section: Introductionmentioning

confidence: 99%

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Involvement of non-LTR retrotransposons in mammal cancer incidence and ageing

Ricci

Peona

Taccioli

2021

Preprint

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The natural occurrence of closely related species that show drastic differences in lifespan and cancer incidence raised the interest in finding the particular adaptations and genomic characteristics underlying the evolution of long lifespans. Studies on transposable elements (TEs) have more and more linked them to ageing and cancer development. In this study, we compared the TE content and dynamics in the genomes of four Rodent and six Chiroptera species that show very different lifespans and cancer susceptibility including the long-lived and refractory to cancer naked mole rat (Heterocephalus glaber), the long-lived fruit bats (Pteropus vampyrus, Rousettus aegypticaus) and the short-lived velvety free-tailed bat (Molossus molossus). By analysing the patterns of recent TE accumulation (TEs that are potentially currently active) in high-quality genome assemblies, we found that the shared genomic characteristics between long-lived species that are refractory to cancer, is the strong suppression, or negative selection against the accumulation, of non-LTR retrotransposons. All the short-lived species did show a recent accumulation of these TEs. Non-LTR retrotransposons have been often found to take part in the immune response of the host against viral infections, but their dysregulation can lead to phenomena of "sterile inflammation" and "inflammageing". Therefore, we hypothesise that the uncontrolled non-LTR retrotransposon activity is an important factor explaining the evolution of shorter lifespans in both Rodents and Chiroptera species and potentially in all mammals. Finally, these results suggest that non-LTR retrotransposons can be agents promoting cancer and ageing in mammals thus they may be targets of future oncological therapies.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

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Involvement of non-LTR retrotransposons in mammal cancer incidence and ageing

Ricci

Peona

Taccioli

2021

Preprint

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“…Studies using knockout mice or cell-based studies using patientderived cells deficient in the regulators of LINE-1 have shed light on the mechanisms by which aberrant activities of LINE-1 can disturb myriad of physiological processes of the host. These include deficiencies in nucleases that degrade LINE-1 cDNA, TREX1, or RNA, ADAR and RNAaseH2; as well as the reader of methylated DNA, MeCP2, and mediators of DNA repair such as TDP-43, SIRT6, and ATM [1][2][3] .…”

Section: Introductionmentioning

confidence: 99%

“…LINE-1 constitutes ~20% of mammalian genomes, and is the only actively replicating retroelement in the human genome 4 . Mounting evidence shows aberrantly high expression and activities of LINE-1 in the context of neurological disorders suggesting the roles of LINE-1 in their etiopathogenesis [1][2][3] . Studies using knockout mice or cell-based studies using patientderived cells deficient in the regulators of LINE-1 have shed light on the mechanisms by which aberrant activities of LINE-1 can disturb myriad of physiological processes of the host.…”

Section: Introductionmentioning

confidence: 99%

LINE-1 activation in the cerebellum drives ataxia

Takahashi

Kudo

Song

et al. 2021

Preprint

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Previous studies have revealed that dysregulation of long interspersed nuclear element 1 (LINE-1), a dominant class of transposable elements in the human genome, correlates with neurodegeneration1–3. Yet whether LINE-1 dysregulation is causal to disease pathogenesis has not been proven directly. Here, we demonstrate that expression of evolutionarily younger LINE-1 families is elevated in the cerebella of ataxia telangiectasia (AT) patients, which was correlated with extensive downregulation of epigenetic silencers. To examine whether LINE-1 activation causes neurologic disease, we established an approach to directly target and activate the promoter of a young family of LINE-1 in mice. LINE-1 activation in the cerebellum was sufficient to lead to robust progressive ataxia. Purkinje cells in the diseased mice exhibited marked electrophysiological dysfunctions and degeneration with a significant accumulation of cytoplasmic ribonucleoprotein LINE-1Orf1p aggregates, endoplasmic reticulum (ER) stress, and DNA damage. Treatment with lamivudine, a nucleoside reverse transcriptase inhibitor, blunted the disease progression by reducing DNA damage, attenuating gliosis and interferon gene signature, and recovering the loss of key functional molecules for calcium homeostasis in Purkinje cells. This study provides direct evidence that young LINE-1 activation drives ataxia phenotype, and points to its pleiotropic effects leading to DNA damage, inflammation, and dysfunction and degeneration of neurons.

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The importance of age‐specific gene expression

Hall

2023

American J of Med Genetics Pt A

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The role of retrotransposable elements in ageing and age-associated diseases

Cited by 202 publications

References 154 publications

Involvement of non-LTR retrotransposons in mammal cancer incidence and ageing

Involvement of non-LTR retrotransposons in mammal cancer incidence and ageing

LINE-1 activation in the cerebellum drives ataxia

The importance of age‐specific gene expression

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