Probing the mechanisms by which endogenous mammalian transposons can disrupt gene expression

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The Ohio State University

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Around half of the mammalian genomes are composed of repetitive elements, of which most are transposable elements (TEs). Although certain TEs or “jumping genes” are still actively mobilized in the mammalian genome, their impact on gene expression remains largely unknown. We have focused on two genes, Slc15a2 in mice and MCC in humans, both of which have been linked recently to TE-mediated gene disruption. This research seeks to study the mechanisms by which such endogenous TE polymorphisms can result in transcriptional disruption. In the case of Slc15a2, we previously reported that a polymorphic endogenous retrovirus (ERV) in intron 7 results in a 13-fold increase of a 1.2 kb prematurely-truncated transcript and a 39-fold decrease in the full-length, 4 kb transcript. This transcriptional disruption further resulted in a 3- to 9- fold down-regulation of the protein, PEPT2. We have also characterized antisense transcripts that were initiated from the bidirectional promoter at the 5’ end of the ERV. In this study, we hypothesized that variable epigenetic regulation at the 5’ long terminal repeat (LTR) of the ERV could be associated with differential antisense transcription, which in turn, could affect variable expression of Slc15a2. To demonstrate this, we used bisulfite sequencing to assess cytosine methylation levels at the ERV, demonstrating a correlation between decreased local DNA methylation and an increase in truncated transcripts at Slc15a2. In the case of human MCC, altered expression in liver cancer samples was recently attributed to three distinct intronic TE polymorphisms. However, our qRT-PCR analysis on a panel of 10 human B-lymphocyte lines from the Coriell repository did not validate this putative association between the presence or absence of TEs and varied expression of MCC. We have also screened 22 primary liver cancer samples for these TEs, to study potential variation in MCC expression, in tumor and matched-normal samples. Again, we could not confirm the reported correlation. We conclude that careful case-by-case analysis is needed to evaluate the many possible biological impacts of TEs on gene expression. Our results suggest that in certain cases epigenetic controls may play a role in the mechanism of TE-mediated transcriptional disruption.


Denman Forum 4th Place - Honorable Mention


Endogenous Transposons, Gene Disruption, Alternative Splicing, Novel Transposon Integrations, Jumping Genes