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Transcriptional regulation of human genes by endogenous retroviral elements Landry, Josette-Renee

Abstract

Human endogenous retroviruses (HERVs) and other long terminal repeat (LTR)- containing elements comprise a significant portion (8%) of the human genome and are likely vestiges of retroviral infections during primate evolution. Although the vast majority of HERVs are now unable to code for retroviral proteins, an unknown number have retained functional transcriptional elements within their LTRs and some of these regulatory sequences have been shown to participate in the transcription of nearby genes. The overall objective of my thesis was to further understand the role of HERVs in human gene regulation by investigating LTRs that provide alternative promoters to cellular genes. When I began my study, three putative endogenous retroviral promoters were identified by screening sequence databases for chimeric (viral-cellular) transcripts. These searches revealed fusion transcripts containing the LTRs of three HERV-E elements linked to the endothelin B receptor (EDNRB), the apolipoprotein C-l (APOC1) and the Opitz syndrome gene, midline 1. To confirm the authenticity of the chimeric transcript and to establish that the mRNAs were transcribed from the retroviral LTRs, we performed 5'RACE and determined the genomic organization for each gene. Our results indicated that the chimeric transcripts were alternatively promoted by the retroviral elements, as they initiated within HERV-E LTRs but spliced into the downstream coding sequence of the cellular genes. To determine the expression pattern and the relative contribution of the retroviral promoter, we quantified the percentage of transcripts which were chimeric in various tissues using real-time PCR. While chimeric APOC1 transcripts could be detected in several tissues tested, the retroviral promoter of EDNRB and MIDI appeared to be placenta-specific. Transient transfection studies supported a role for the EDNRB and MIDI LTRs as strong promoters in placenta and suggested a function for the LTRs as enhancers. Further deletion and hybrid constructs delineated regions within both LTRs necessary for strong promoter activity. Finally, to further characterize the APOC1, EDNRB and MIDI genes, the non-retro viral (native) promoters of these three genes were also analysed. These findings provide further evidence that some endogenous retroviruses have evolved a biological function as transcriptional regulatory elements by contributing alternative promoters to human genes.

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