The Role of Somatic L1 Retrotransposition in Human Cancers

Scott, Emma C.; Devine, Scott E.

doi:10.3390/v9060131

Cited by 79 publications

(75 citation statements)

References 101 publications

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“…Moreover, retrotransposition does not normally occur in somatic cells because the repeats are strongly silenced by a high degree of methylation [53,54], but in high-stress conditions the methylation level can decrease and the LINE1 transcription can influence the intron retention [20,[55][56][57][58].…”

Section: Discussionmentioning

confidence: 99%

“…Since these genomic modifications may be harmful, the host cell is provided with several mechanisms to suppress dangerous retrotransposon activity [53,54], among which one of the main known is the methylation of CpG sequences in the LINE-1 5 UTR. In fact, a general LINE-1 methylation decrease has been observed in case of intense stress conditions such as many cancer types [58] and neurological disorders and, indeed, the retrotransposition is demonstrated only in few tissues (germinal and nervous tissues) [38,61].…”

Section: Discussionmentioning

confidence: 99%

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Gallop Racing Shifts Mature mRNA towards Introns: Does Exercise-Induced Stress Enhance Genome Plasticity?

Cappelli

Mecocci

Gioiosa³

et al. 2020

Genes

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Physical exercise is universally recognized as stressful. Among the "sport species", the horse is probably the most appropriate model for investigating the genomic response to stress due to the homogeneity of its genetic background. The aim of this work is to dissect the whole transcription modulation in Peripheral Blood Mononuclear Cells (PBMCs) after exercise with a time course framework focusing on unexplored regions related to introns and intergenic portions. PBMCs NGS from five 3 year old Sardinian Anglo-Arab racehorses collected at rest and after a 2000 m race was performed. Apart from differential gene expression ascertainment between the two time points the complexity of transcription for alternative transcripts was identified. Interestingly, we noted a transcription shift from the coding to the non-coding regions. We further investigated the possible causes of this phenomenon focusing on genomic repeats, using a differential expression approach and finding a strong general up-regulation of repetitive elements such as LINE. Since their modulation is also associated with the "exonization", the recruitment of repeats that act with regulatory functions, suggesting that there might be an active regulation of this transcriptional shift. Thanks to an innovative bioinformatic approach, our study could represent a model for the transcriptomic investigation of stress.Genes 2020, 11, 410 2 of 15 in humans [1] and in animals with other ongoing initiatives such Functional Annotation of Animal Genomes (FAANG) [2].Despite new knowledge has been produced and genome annotations significantly improved, the genome response, in terms of gene expression modulation, is far from being understood. The big annotation projects, with some exceptions (FANTOM Projects [3]), focused mostly on "spatial" variation, intended as variation of expression in different cells and tissues, while the "temporal" one, physiological and pathological variation through time, has been left behind. This is particularly true for "non-model" species.Also different studies (Genome Wide Association Studies-GWAS) pointed towards the intergenic and intronic fraction of the genome [4] where the most regulatory molecules lie and are transcribed.One of the most promising approach in the dissection of the molecular basis of a phenotype is the Expression Quantitative Trait Loci (eQTL), where variations on gene expression are associated to specific regions or variants in the DNA. Studies in eQTL are already possible and are being applied, but the real step forward in functional genomics could be made by analyzing temporal data other than only the spatial ones, understanding "when" and "how much" the existing DNA variation could affect the transcriptional machinery, and therefore the phenotype. This is especially true when we are facing with biological problems involving a complex multi-organ process such exercise and stress related organism response.Time-course experiments may allow to fully understand the functional response of the genome to stimuli when pathway...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Gallop Racing Shifts Mature mRNA towards Introns: Does Exercise-Induced Stress Enhance Genome Plasticity?

Cappelli

Mecocci

Gioiosa³

et al. 2020

Genes

View full text Add to dashboard Cite

show abstract

“…Evidence for L1 mobilization in cancers is largely restricted to tumors of epithelial origin, with somatic L1 insertions conspicuously infrequent in brain and blood cancers (Iskow et al 2010;Lee et al 2012;Achanta et al 2016;Carreira et al 2016). Thus, some cancer cell types may be intrinsically susceptible to L1 retrotransposition (Carreira et al 2014;Scott and Devine 2017).…”

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confidence: 99%

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

et al. 2018

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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.

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“…The viral protein kinases are emerging as important players in gammaherpesvirus-associated lymphomagenesis, and an intriguing possibility is that its activation of Pol III retrotransposons—which are known to cause insertional mutagenesis [69–71] — may contribute to this phenotype. Indeed, prolonged expression of the ORF36 homolog in EBV (BGLF4) can contribute to genome instability leading to tumor formation, which has been linked to its phosphorylation of lamin A/C and topoisomerase-II [72, 73].…”

Section: Discussionmentioning

confidence: 99%

The conserved herpesviral kinase ORF36 activates B2 retrotransposons during murine gammaherpesvirus infection

Schaller

Tucker

Willis

et al. 2020

Preprint

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ABSTRACTShort interspersed nuclear elements (SINEs) are RNA polymerase III (RNAPIII) transcribed, retrotransposable noncoding RNA (ncRNA) elements ubiquitously spread throughout mammalian genomes. While normally silenced in healthy somatic tissue, SINEs can be induced during infection with DNA viruses, including the model murine gammaherpesvirus MHV68. Here, we explored the mechanisms underlying MHV68 activation of SINE ncRNAs. We demonstrate that lytic MHV68 infection of B cells, macrophages and fibroblasts leads to robust activation of the B2 family of SINEs in a cell autonomous manner. B2 ncRNA induction requires neither host innate immune signaling factors nor involvement of the RNAPIII master regulator Maf1. However, we identify MHV68 ORF36, the conserved herpesviral kinase, as playing a key role in B2 induction during lytic infection. SINE activation is linked to ORF36 kinase activity and can also be induced by HDAC1/2 inhibition, which is one of the known ORF36 functions. Collectively, our data suggest that ORF36-mediated changes in chromatin modification contribute to B2 activation during MHV68 infection, and that this activity is conserved in other herpesviral protein kinase homologs.AUTHOR SUMMARYViral infection dramatically changes the levels of many types of RNA in a cell. In particular, certain oncogenic viruses activate expression of repetitive genes called retrotransposons, which are normally silenced due to their ability to copy and spread throughout the genome. Here, we established that infection with the gammaherpesvirus MHV68 leads to a dramatic induction of a class of noncoding retrotransposons called B2 SINEs in multiple cell types. We then explored how MHV68 activates B2 SINEs, revealing a role for the conserved herpesviral protein kinase ORF36. Both ORF36 kinase-dependent and kinase-independent functions contribute to B2 induction, perhaps through ORF36 targeting of proteins involved in controlling the accessibility of chromatin surrounding SINE loci. Understanding features underlying induction of these elements following MHV68 infection should provide insight into core elements of SINE regulation, as well as dis-regulation of SINE elements associated with disease.

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The Role of Somatic L1 Retrotransposition in Human Cancers

Cited by 79 publications

References 101 publications

Gallop Racing Shifts Mature mRNA towards Introns: Does Exercise-Induced Stress Enhance Genome Plasticity?

Gallop Racing Shifts Mature mRNA towards Introns: Does Exercise-Induced Stress Enhance Genome Plasticity?

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

The conserved herpesviral kinase ORF36 activates B2 retrotransposons during murine gammaherpesvirus infection

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