Activation of individual L1 retrotransposon instances is restricted to cell-type dependent permissive loci

Philippe, Claude; Vargas-Landin, Dulce B; Doucet, Aurélien J.; Essen, Dominic van; Vera-Otárola, Jorge; Kuciak, Monika; Corbin, Antoine; Nigumann, Pilvi; Cristofari, Gaël

doi:10.7554/elife.13926

Cited by 140 publications

(220 citation statements)

References 101 publications

Supporting

Mentioning

194

Contrasting

Order By: Relevance

“…Among these, one insertion originated from a donor L1 on Chromosome 22 previously found to be responsible for tumor-specific L1 insertions in other human cancer types (Pitkanen et al 2014;Tubio et al 2014;Paterson et al 2015). An increasing body of evidence suggests that a particular subset of retrotransposition-competent L1 loci tend to be recurrent contributors to genomic instability in human malignancies and cancer cell lines (Tubio et al 2014;Philippe et al 2016;Scott et al 2016;Gardner et al 2017). Indeed, here we found that the promoter region of the TTC28 donor L1 was largely demethylated in both nontumor liver and matched ICC tumor cells, as a prior study found for a Chromosome 17 donor L1 responsible for APC exon mutagenesis in a colorectal cancer patient (Scott et al 2016).…”

Section: Discussionsupporting

confidence: 81%

“…Analysis of the 3 ′ transduced sequence identified a donor L1 on Chromosome 22 and intronic to the gene TTC28. Recent studies of 3 ′ transduction-bearing L1 insertions in tumor samples pointed to this element as a highly active donor L1 in human tumor cells (Pitkanen et al 2014;Tubio et al 2014;Paterson et al 2015;Philippe et al 2016;Gardner et al 2017). We therefore performed targeted bisulfite sequencing of the complete donor L1 promoter region, which was significantly demethylated in patient ICC.75 tumor compared to matched nontumor liver (P < 0.0001, paired t-test, two tailed) (Fig.…”

Section: A D C Bmentioning

confidence: 98%

See 1 more Smart Citation

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

et al. 2018

View full text Add to dashboard Cite

The retrotransposon Long Interspersed Element 1 (LINE-1 or L1) is a continuing source of germline and somatic mutagenesis in mammals. Deregulated L1 activity is a hallmark of cancer, and L1 mutagenesis has been described in numerous human malignancies. We previously employed retrotransposon capture sequencing (RC-seq) to analyze hepatocellular carcinoma (HCC) samples from patients infected with hepatitis B or hepatitis C virus and identified L1 variants responsible for activating oncogenic pathways. Here, we have applied RC-seq and whole-genome sequencing (WGS) to an Abcb4 (Mdr2)−/− mouse model of hepatic carcinogenesis and demonstrated for the first time that L1 mobilization occurs in murine tumors. In 12 HCC nodules obtained from 10 animals, we validated four somatic L1 insertions by PCR and capillary sequencing, including T F subfamily elements, and one G F subfamily example. One of the T F insertions carried a 3 ′ transduction, allowing us to identify its donor L1 and to demonstrate that this full-length T F element retained retrotransposition capacity in cultured cancer cells. Using RC-seq, we also identified eight tumor-specific L1 insertions from 25 HCC patients with a history of alcohol abuse. Finally, we used RC-seq and WGS to identify three tumor-specific L1 insertions among 10 intra-hepatic cholangiocarcinoma (ICC) patients, including one insertion traced to a donor L1 on Chromosome 22 known to be highly active in other cancers. This study reveals L1 mobilization as a common feature of hepatocarcinogenesis in mammals, demonstrating that the phenomenon is not restricted to human viral HCC etiologies and is encountered in murine liver tumors.

show abstract

Section: Discussionsupporting

confidence: 81%

Section: A D C Bmentioning

confidence: 98%

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Susceptibility to LINE-1 hypomethylation appears to be cell and tissue specific and might be dependent on cancer type or subsets of a specific cancer type 53–55 . Moreover, emerging evidence suggest that not all LINE-1s are regulated in the same way 56 . Global LINE-1 methylation studies are unable to provide evidence for a relationship between methylation at individual LINE-1 and their activity.…”

Section: Discussionmentioning

confidence: 99%

Decoupling of DNA methylation and activity of intergenic LINE-1 promoters in colorectal cancer

et al. 2017

View full text Add to dashboard Cite

Hypomethylation of LINE-1 repeats in cancer has been proposed as the main mechanism behind their activation; this assumption, however, was based on findings from early studies that were biased toward young and transpositionally active elements. Here, we investigate the relationship between methylation of 2 intergenic, transpositionally inactive LINE-1 elements and expression of the LINE-1 chimeric transcript (LCT) 13 and LCT14 driven by their antisense promoters (L1-ASP). Our data from DNA modification, expression, and 5′RACE analyses suggest that colorectal cancer methylation in the regions analyzed is not always associated with LCT repression. Consistent with this, in HCT116 colorectal cancer cells lacking DNA methyltransferases DNMT1 or DNMT3B, LCT13 expression decreases, while cells lacking both DNMTs or treated with the DNMT inhibitor 5-azacytidine (5-aza) show no change in LCT13 expression. Interestingly, levels of the H4K20me3 histone modification are inversely associated with LCT13 and LCT14 expression. Moreover, at these LINE-1s, H4K20me3 levels rather than DNA methylation seem to be good predictor of their sensitivity to 5-aza treatment. Therefore, by studying individual LINE-1 promoters we have shown that in some cases these promoters can be active without losing methylation; in addition, we provide evidence that other factors (e.g., H4K20me3 levels) play prominent roles in their regulation.

show abstract

“…Their analysis involves integrating a combination of data types, including a genomic LINE-1 insertion map, RNA-seq reads, and chromatin immunoprecipitation (ChIP)-seq data (65). Actively transcribed LINE-1 loci have a two-part ‘signature’ : (i.)…”

Section: Introductionmentioning

confidence: 99%

The Human Long Interspersed Element-1 Retrotransposon: An Emerging Biomarker of Neoplasia

et al. 2017

View full text Add to dashboard Cite

Background A large portion of intronic and intergenic space in our genome consists of repeated sequences. One of the most prevalent is the Long INterspersed Element-1 (LINE-1, L1) mobile DNA. LINE-1 is rightly receiving increasing interest as a cancer biomarker. Content Intact LINE-1 elements are self-propagating. They code for RNA and proteins which function to make more copies of the genomic element. Our current understanding is that this process is repressed in most normal cells, but that LINE-1 expression is a hallmark of many types of malignancy. Here, we will consider features of cancer cells when cellular defense mechanisms repressing LINE-1 go awry. We will review evidence that genomic LINE-1 methylation, LINE-1-encoded RNAs, and LINE-1 open reading frame 1 protein (ORF1p) may be useful in cancer diagnosis. Summary The repetitive and variable nature of LINE-1 DNA sequences pose unique challenges to studying them, but recent advances in reagents and next generation sequencing present opportunities to characterize LINE-1 expression and activity in cancers, and identify clinical applications.

show abstract

Activation of individual L1 retrotransposon instances is restricted to cell-type dependent permissive loci

Cited by 140 publications

References 101 publications

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

Decoupling of DNA methylation and activity of intergenic LINE-1 promoters in colorectal cancer

The Human Long Interspersed Element-1 Retrotransposon: An Emerging Biomarker of Neoplasia

Contact Info

Product

Resources

About