Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition

Rodríguez-Martín, Bernardo; Alvarez, Eva G.; Baez‐Ortega, Adrian; Zamora, Jorge; Supek, Fran; Demeulemeester, Jonas; Santamarina, Martin; Ju, Young Seok; Temes, Javier; García‐Souto, Daniel; Detering, Harald; Li, Yilong; Rodríguez-Castro, Jorge Homero; Dueso-Barroso, Ana; Bruzos, Alicia L.; Dentro, Stefan C.; Blanco, Miguel; Contino, Gianmarco; Ardeljan, Daniel; Tojo, Marta; Roberts, Nicola D.; Zumalave, Sonia; Edwards, Paul A.W.; Weischenfeldt, Joachim; Puiggròs, Montserrat; Chong, Zechen; Chen, Ken; Lee, Eunjung Alice; Wala, Jeremiah A.; Raine, Keiran; Butler, Adam; Waszak, Sebastian M.; Navarro, Fábio C. P.; Schumacher, Steven E.; Monlong, Jean; Maura, Francesco; Bolli, Niccolò; Bourque, Guillaume; Gerstein, Mark; Park, Peter J.; Wedge, David C.; Beroukhim, Rameen; Torrents, David; Korbel, Jan O.; Martincorena, Iñigo; Fitzgerald, Rebecca C.; Loo, Peter Van; Kazazian, Haig H.; Burns, Kathleen H.; Campbell, Peter J.; Tubío, José M. C.

doi:10.1038/s41588-019-0562-0

Cited by 286 publications

(333 citation statements)

References 59 publications

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“…Retrotransposition activity is high in early embryo (26) and brain (37) during normal development, so potential integration of coronavirus sequence into human genome is suggested to be scrutinized for these cells. It was also reported that retrotransposon upregulation is positively correlated with tumor progression (38), causing genomic deletion, translocation and duplication (39). What's more, increased expression of retrotransposon LINE-1 contributes to age-associated in ammation in several tissues (40).…”

Section: The Model Of Coronavirus-retrotransposon Interactionmentioning

confidence: 96%

Exogenous coronavirus interacts with endogenous retrotransposon in human cells

Yin

Liu

et al. 2020

Preprint

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Abstract Background: There is an increased global outbreak of diseases caused by coronaviruses affecting respiratory tracts of birds and mammals. Recent particularly dangerous coronaviruses are MERS-CoV, SARS-CoV and SARS-CoV-2, causing respiratory illness and even failure of several organs. However, profound impact of coronavirus on host cells remains elusive. Results: Here, we go deep into transcriptome of MERS-CoV, SARS-CoV and SARS-CoV-2 infected human lung-derived cells, and observed that infection of these coronaviruses all induced increase of retrotransposon expression through upregulation of TET genes. Similar upregulation of retrotransposon was also observed in SARS-CoV-2 infected human intestinal organoids. Retrotransposon upregulation will lead to increased genome instability and more frequent readthrough from retrotransposon to dysregulate gene expression. People with higher basal level of retrotransposon like cancer patients and aged people will have increased risk of symptomatic infection. Additionally, we show evidence supporting long-term epigenetic inheritance of retrotransposon upregulation. We also observed significant amount of chimeric transcripts of retrotransposon and SARS-CoV-2 RNA for potential human genome invasion of viral fragments, with the front and the rear part of SARS-CoV-2 genome being easier to form chimeric RNA, and this may apply for other coronaviruses. Here we suggest that primers and probes for nucleic acid detection should be designed in the middle of virus genome to identify live virus with higher probability. Conclusions: In summary, we propose that infection of coronaviruses especially SARS-CoV-2 induce retrotransposon activation, formation of chimeric coronavirus-retrotransposon RNA, and elicits more severe symptoms in patients with underlying diseases. More attention may need to be paid to potential harm contributed by retrotransposon dysregulation in treatment of coronavirus-infected patients.

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Section: The Model Of Coronavirus-retrotransposon Interactionmentioning

confidence: 96%

Exogenous coronavirus interacts with endogenous retrotransposon in human cells

Yin

Liu

et al. 2020

Preprint

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“…61 5b-d, Supplementary Table 2). For example, an L1Hs located intronic to the TTC28 gene 62 and known to be mobile in liver and other cancers [24][25][26] was hypomethylated in CTRL-5413 63 liver ( Fig. 1d).…”

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confidence: 99%

Nanopore sequencing enables comprehensive transposable element epigenomic profiling

Ewing

Smits

Sánchez‐Luque

et al. 2020

Preprint

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1 We apply long-read nanopore sequencing and a new tool, TLDR (Transposons from Long 2 Dirty Reads), to directly infer CpG methylation of new and extant human transposable 3 element (TE) insertions in hippocampus, heart, and liver, as well as paired tumour and non-4 tumour liver. Whole genome TLDR analysis greatly facilitates studies of TE biology as 5 complete insertion sequences and their epigenetic modifications are readily obtainable. 6 7 Main 8Transposable elements (TEs) pervade our genomic architecture and broadly influence 9 human biology and disease 1 . Recently, Oxford Nanopore Technologies (ONT) long-read 10

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“…Reflecting enrichment in CNV high subtype, our LINE-1 ORF1p quantification (hereafter called LINE-1 expression) is highly correlated with genome-wide CNV (Spearman ρ=0.44, p=3.6x10 -5 , figure 4B). Strong correlation between the somatic LINE-1 insertions and structural variation was recently reported in a pan cancer study of whole genomes (Rodriguez-Martin et al, 2020) . In our data, this correlation is only partially explained by p53 mutation (partial Spearman ρ=0.31, p=0.004), suggesting that LINE-1 may have a more direct role in CNV generation and that this effect may be enhanced by the effect of p53 mutation/deletion.…”

Section: Atm-mrn-smc Signalling Cnv and Drivers Of Cell Cycle Progrementioning

confidence: 58%

“…It still remains to be shown that a similar interaction between LINE-1 expression and replication stress occurs in actual human cancers. Another recent study (Rodriguez-Martin et al, 2020), which looked at somatic LINE-1 insertions in nearly 3000 cancer genomes, did identify correlations between LINE-1 insertion and multiple classes of structural variation, including several instances where a structural variation could directly be attributed at an improperly repaired retrotransposition intermediate. These results provide support for a widespread LINE-1 / DNA damage relationship in cancer, but do not elucidate the changes in expression and signalling that are involved.…”

Section: Introductionmentioning

confidence: 99%

LINE-1 expression in cancer correlates with DNA damage response, copy number variation, and cell cycle progression

McKerrow

Wang

Mita

et al. 2020

Preprint

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Retrotransposons are genomic DNA sequences that are capable of copying themselves to new genomic locations via RNA intermediates; LINE-1 is the only retrotransposon that remains autonomous and active in the human genome. The mobility of LINE-1 is largely repressed in somatic tissues, but LINE-1 is active in many cancers. Recent studies using LINE-1 constructs indicate that host cells activate a DNA damage response (DDR) to repair retrotransposition intermediates and resolve conflicts between LINE-1 and DNA replication. Using multi-omic data from the CPTAC project, we found correlations between LINE-1 expression and ATM-MRN-SMC DDR signalling in endometrial cancer and between LINE-1 and the ATR-CHEK1 pathway in p53 wild type breast cancer. This provides evidence that conflicts between LINE-1 and DNA replication occur in at least some human cancers. Furthermore, LINE-1 expression in these cancers is correlated with the total amount of copy number variation genome wide, indicating that, when active in cancer, pointing to a direct impact of LINE-1 associated DNA damage on genome structure. We also find that, in endometrial and ovarian cancer, LINE-1 expression is correlated with the expression of genes that drive cycle progression including E2F3, PLK1 and Aurora kinase B. This study provides evidence, supporting recent work in model cell lines, of a LINE-1/DDR connection in human tumors and raises the possibility of additional interactions between LINE-1 and the cell cycle.

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Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition

Cited by 286 publications

References 59 publications

Exogenous coronavirus interacts with endogenous retrotransposon in human cells

Exogenous coronavirus interacts with endogenous retrotransposon in human cells

Nanopore sequencing enables comprehensive transposable element epigenomic profiling

LINE-1 expression in cancer correlates with DNA damage response, copy number variation, and cell cycle progression

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