Selective inhibition of Alu retrotransposition by APOBEC3G

Esophageal adenocarcinoma (EAC) has one of the fastest increases in incidence of any cancer, along with poor five-year survival rates. Barrett's esophagus (BE) is the main risk factor for EAC; however, the mechanisms driving EAC development remain poorly understood. Here, transcriptomic profiling was performed using RNA-sequencing (RNA-seq) on premalignant and malignant Barrett's tissues to better understand this disease. Machine-learning and network analysis methods were applied to discover novel driver genes for EAC development. Identified gene expression signatures for the distinction of EAC from BE were validated in separate datasets. An extensive analysis of the noncoding RNA (ncRNA) landscape was performed to determine the involvement of novel transcriptomic elements in Barrett's disease and EAC. Finally, transcriptomic mutational investigation of genes that are recurrently mutated in EAC was performed. Through these approaches, novel driver genes were discovered for EAC, which involved key cell cycle and DNA repair genes, such as BRCA1 and PRKDC. A novel 4-gene signature (CTSL, COL17A1, KLF4, and E2F3) was identified, externally validated, and shown to provide excellent distinction of EAC from BE. Furthermore, expression changes were observed in 685 long noncoding RNAs (lncRNA) and a systematic dysregulation of repeat elements across different stages of Barrett's disease, with wide-ranging downregulation of Alu elements in EAC. Mutational investigation revealed distinct pathways activated between EAC tissues with or without TP53 mutations compared with Barrett's disease. In summary, transcriptome sequencing revealed altered expression of numerous novel elements, processes, and networks in EAC and premalignant BE.Implications: This study identified opportunities to improve early detection and treatment of patients with BE and esophageal adenocarcinoma. Mol Cancer Res; 15(11); 1558-69. Ó2017 AACR.

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“…5B). This latter finding is especially interesting as we also found that APOBEC3G, an inhibitor of SINE elements (37) (38). In Figure 4.…”

Section: Long Noncoding Rnas Show Characteristic Differential Expresssupporting

confidence: 61%

Novel Aberrations Uncovered in Barrett's Esophagus and Esophageal Adenocarcinoma Using Whole Transcriptome Sequencing

Mååg

Fisher

Levert-Mignon³

et al. 2017

Molecular Cancer Research

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“…The integration of new SINE copies often disturbs gene expression; on the other hand, they can serve as a source of genomic innovations and a factor of genome plasticity (Makalowski, 2000). Nevertheless, the organism tries to suppress SINE amplification using, for example, APOBEC3-mediated system (Chiu et al, 2006;Hulme et al, 2007) or SINE DNA methylation (Rubin et al, 1994). As LINE RT is required for SINE amplification, LINE repression also protects the genome from SINE expansion.…”

Section: Overview Of Sine Evolutionmentioning

confidence: 99%

Origin and evolution of SINEs in eukaryotic genomes

2011

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“…It is possible that ORF1p helps Alu insertion in a similar manner. There are observed differences between SINE and LINE amplification and regulation (Hulme et al, 2007). Further analysis of the differential role that ORF1p plays in SINE vs. LINE mobilization could be instrumental in demonstrating how their amplification pathways deviate.…”

Section: Model Of Potential Of Orf1p Role In Sine Retrotranspositionmentioning

confidence: 99%

“…A potential L1 ORF1p function in TPRT has been suggested (Martin and Bushman 2001) and may exist in other non-LTR elements with very different ORF1 proteins (Matsumoto et al, 2006), but a direct role has not been established. Although ORF1p is essential for L1 retrotransposition and likely aids trans-mobilization of other elements such as U6 (GarciaPerez et al, 2007) and processed pseudogenes (Esnault et al, 2000;Wei et al, 2001), Alu retrotransposition in cultured HeLa cells is observed when supplemented with L1 elements lacking functional ORF1p (Dewannieux et al, 2003;Hulme et al, 2007). While these experiments suggest that ORF1p is not essential for Alu retrotransposition, the endogenously expressed ORF1 in HeLa cells, leaves the possibility that low levels of ORF1p are required for Alu mobilization.…”

Section: Introductionmentioning

confidence: 99%

LINE-1 ORF1 protein enhances Alu SINE retrotransposition

Wallace

Wagstaff

Deininger

et al. 2008

Gene

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Retroelements have contributed over one third of the human genome mass. The currently active LINE-1 (L1) codes for two proteins (ORF1p and ORF2p), both strictly required for retrotransposition. In contrast, the non-coding parasitic SINE (Alu) only appears to need the L1 ORF2p for its own amplification. This requirement was previously determined using a tissue culture assay system in human cells (HeLa). Because HeLa are likely to express functional L1 proteins, it is possible that low levels of endogenous ORF1p are necessary for the observed tagged Alu mobilization. By individually expressing ORF1 and ORF2 proteins from both human (L1 RP and LRE3) and rodent (L1 A102 and L1 spa ) L1 sources, we demonstrate that increasing amounts of ORF1 expressing vector enhances tagged Alu mobilization in HeLa cells. In addition, using chicken fibroblast cells as an alternate cell culture source, we confirmed that ORF1p is not strictly required for Alu mobilization in our assay. Supporting our observations in HeLa cells, we find that tagged Alu retrotransposition is improved by supplementation of ORF1p in the cultured chicken cells. We postulate that L1 ORF1p plays either a direct or indirect role in enhancing the interaction between the Alu RNA and the required factors needed for its retrotransposition.

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Selective inhibition of Alu retrotransposition by APOBEC3G

Cited by 142 publications

References 53 publications

Novel Aberrations Uncovered in Barrett's Esophagus and Esophageal Adenocarcinoma Using Whole Transcriptome Sequencing

Novel Aberrations Uncovered in Barrett's Esophagus and Esophageal Adenocarcinoma Using Whole Transcriptome Sequencing

Origin and evolution of SINEs in eukaryotic genomes

LINE-1 ORF1 protein enhances Alu SINE retrotransposition

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