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Activation of an endogenous retrovirus enhancer by insertion into a heterologous context.

ABSTRACT: An enhancer element is located in the U3 portion of exogenous avian retrovirus long terminal repeats (LTRs). A similar element has not been detected in the LTRs of ev-1 and ev-2, two avian endogenous viruses (evs) that normally are not expressed in vivo. Experiments were initiated to determine whether minor nucleotide differences in the U3 region of a previously untested ev that is ubiquitously expressed in vivo (ev-3) might confer enhancer function on the LTR of this provirus. This question was addressed by inserting U3 regions from ev-3 and from ev-1 and/or ev-2 both upstream of the herpesvirus thymidine kinase gene promoter and in place of the major enhancer domains of the Rous sarcoma virus LTR and determining their relative effects on transcription. U3 regions from all evs tested were unable to enhance transcription from the thymidine kinase gene promoter, indicating that nucleotide differences in the ev U3 regions do not affect their relative enhancer function and therefore are unlikely to play a role in their differential expression in vivo. Unexpectedly, however, all ev U3 regions were able to augment transcription in an orientation-independent manner in the ev-Rous sarcoma virus hybrid LTRs. Further experiments conducted to determine why this enhancer activity is not detectable in intact ev LTRs demonstrated that it was not due to removal of repressor sequences in the ev fragments used that might normally be present in intact ev LTRs. The lack of detectable enhancer activity in intact ev LTRs also was not explained by a defect in ev promoters that makes them unresponsive to enhancers in cis. These experiments therefore identify sequences that, although unable to function detectably as enhancers in their natural context, can function efficiently in a heterologous context. Data are discussed in terms of the modularity of enhancer elements and possible interactions between enhancers and promoter-specific sequences.

SUBMITTER: Conklin KF

PROVIDER: S-EPMC240608 | biostudies-other | 1991 May

REPOSITORIES: biostudies-other

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Activation of an endogenous retrovirus enhancer by insertion into a heterologous context.

Conklin K F KF

Journal of virology 19910501 5

An enhancer element is located in the U3 portion of exogenous avian retrovirus long terminal repeats (LTRs). A similar element has not been detected in the LTRs of ev-1 and ev-2, two avian endogenous viruses (evs) that normally are not expressed in vivo. Experiments were initiated to determine whether minor nucleotide differences in the U3 region of a previously untested ev that is ubiquitously expressed in vivo (ev-3) might confer enhancer function on the LTR of this provirus. This question was ...[more]

PMID: 1850026

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Project description:BACKGROUND: Long non-coding RNAs (lncRNAs) are emerging as molecules that significantly impact many cellular processes and have been associated with almost every human cancer. Compared to protein-coding genes, lncRNA genes are often associated with transposable elements, particularly with endogenous retroviral elements (ERVs). ERVs can have potentially deleterious effects on genome structure and function, so these elements are typically silenced in normal somatic tissues, albeit with varying efficiency. The aberrant regulation of ERVs associated with lncRNAs (ERV-lncRNAs), coupled with the diverse range of lncRNA functions, creates significant potential for ERV-lncRNAs to impact cancer biology. METHODS: We used RNA-seq analysis to identify and profile the expression of a novel lncRNA in six large cohorts, including over 7,500 samples from The Cancer Genome Atlas (TCGA). RESULTS: We identified the tumor-specific expression of a novel lncRNA that we have named Endogenous retroViral-associated ADenocarcinoma RNA or 'EVADR', by analyzing RNA-seq data derived from colorectal tumors and matched normal control tissues. Subsequent analysis of TCGA RNA-seq data revealed the striking association of EVADR with adenocarcinomas, which are tumors of glandular origin. Moderate to high levels of EVADR were detected in 25 to 53% of colon, rectal, lung, pancreas and stomach adenocarcinomas (mean?=?30 to 144 FPKM), and EVADR expression correlated with decreased patient survival (Cox regression; hazard ratio?=?1.47, 95% confidence interval?=?1.06 to 2.04, P?=?0.02). In tumor sites of non-glandular origin, EVADR expression was detectable at only very low levels and in less than 10% of patients. For EVADR, a MER48 ERV element provides an active promoter to drive its transcription. Genome-wide, MER48 insertions are associated with nine lncRNAs, but none of the MER48-associated lncRNAs other than EVADR were consistently expressed in adenocarcinomas, demonstrating the specific activation of EVADR. The sequence and structure of the EVADR locus is highly conserved among Old World monkeys and apes but not New World monkeys or prosimians, where the MER48 insertion is absent. Conservation of the EVADR locus suggests a functional role for this novel lncRNA in humans and our closest primate relatives. CONCLUSIONS: Our results describe the specific activation of a highly conserved ERV-lncRNA in numerous cancers of glandular origin, a finding with diagnostic, prognostic and therapeutic implications.

Dataset Information

Activation of an endogenous retrovirus enhancer by insertion into a heterologous context.

Publications

Activation of an endogenous retrovirus enhancer by insertion into a heterologous context.

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