<i>Sleeping Beauty</i>transposon system for genetic etiological research and gene therapy of cancers

Hou, Xiaomei; Du, Yan; Deng, Yang; Wu, Jianfeng; Cao, Guangwen

doi:10.4161/15384047.2014.986944

Cited by 16 publications

(19 citation statements)

References 86 publications

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“…Although ignoring these integration events, which account for ~ 1% of total integrations, does not change the conclusions of previous studies of SB integration, these low-frequency events have important consequences nonetheless. Recent studies have explored the use of SB in gene therapy [ 17 , 18 ]. Rare integrations in non-TA sites need to be considered in these experiments to minimize the possibility of unexpected insertions disrupting gene functions.…”

Section: Discussionmentioning

confidence: 99%

Sleeping Beauty transposon integrates into non-TA dinucleotides

Guo

Zhang

2018

Mobile DNA

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BackgroundSleeping Beauty transposon (SB) has become an increasingly important genetic tool for generating mutations in vertebrate cells. It is widely thought that SB exclusively integrates into TA dinucleotides. However, this strict TA-preference has not been rigorously tested in large numbers of insertion sites that now can be detected with next generation sequencing. Li et al. found 71 SB insertions in non-TA dinucleotides in 2013, suggesting that TA dinucleotides are not the only sites of SB integration, yet further studies on this topic have not been carried out.ResultsIn this study, we re-analyzed 600 million pairs of Illumina sequence reads from a high-throughput SB mutagenesis screen and identified 28 thousand SB insertions in non-TA sites. We recovered some of these non-TA sites using PCR and confirmed that at least a subset of the insertions at non-TA sites are real integrations. The consensus sequence of these non-TA sites shows an asymmetric pattern distinct from the symmetric pattern of the canonical TA sites. Perfect similarity between the downstream flanking sequence and SB transposon ends indicates there may be interaction between the transposon DNA binding domain of transposase and the target DNA.ConclusionThe TA-preference of SB transposon is not as strict as what people had thought. And the SB integrations at non-TA sites might be guided by the interaction between the transposon DNA binding domain of SB transposase and the target DNA.Electronic supplementary materialThe online version of this article (10.1186/s13100-018-0113-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Sleeping Beauty transposon integrates into non-TA dinucleotides

Guo

Zhang

2018

Mobile DNA

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“…The methylation level of the RTL1 promoter is significantly lower in lung cancer tissues than in normal lung tissues. Further, the expression of microRNAs in the exon of RTL1 is increased [ 10 ], and RTL1 is highly expressed in mouse liver cancer induced by the Sleeping Beauty (SB) gene [ 11 ]. Because RTL1 is the only consistently altered gene detected in all SB-induced tumours with Dlk1-Dio3 integrations, it has been suggested that RTL1 activation is a driver of liver cancer [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

RTL1 promotes melanoma proliferation by regulating Wnt/β-catenin signalling

Fan

Ye²,

Zhu³

et al. 2017

Oncotarget

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Cutaneous melanoma is a highly malignant and metastatic skin cancer with high mortality. However, its underlying mechanisms remain largely unclear. Here, we found that retrotransposon-like 1 (RTL1) is highly enriched in melanoma tissue, especially in early and horizontal growth tissues. Knockdown of RTL1 in melanoma cells resulted in cell proliferation suppression; cell cycle arrest at G1 phase; and down-regulation of E2F1, CYCLIN D1, cyclin-dependent kinase 6 (CDK6) and c-MYC. Moreover, overexpression of RTL1 in melanoma cells accelerated cell proliferation, promoted passage of the cell cycle beyond G1 phase, and increased the expression of cell cycle related genes. Mechanistically, we found that knockdown of RTL1 inhibited the Wnt/β-Catenin pathway by regulating the expression of genes specifically involved in β-CATENIN stabilization. Furthermore, the overexpression and knockdown of β-CATENIN rescued the effects of RTL1 on melanoma cell proliferation and the cell cycle. These findings were also confirmed via tumour xenografts in nude mice. Together, our results demonstrated that RTL1 promotes melanoma cell proliferation by regulating the Wnt/β-Catenin signalling pathway.

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“…14 Also, several experimental studies in model organisms repeatedly demonstrated a potential application of the SB system in cancer gene therapy, for example, for metastatic CRC or glioblastoma. 15 Taken together, the work by Kodama et al nicely demonstrates the usefulness of the SB transposon system in Figure 1. Mechanisms of the 2-step forward genetic screen in mice using the sleeping beauty transposon system and short hairpin RNA (shRNA) library screening.…”

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confidence: 76%