3 years ago

Mechanisms of HERV-K (HML-2) transcription during human mammary epithelial cell transformation.

Zachary H Williams, Neeru Bhardwaj, John M Coffin, Charlotte Kuperwasser, Meagan Montesion
Increasing evidence suggests that repetitive elements may play a role in host gene regulation, particularly through the donation of alternative promoters, enhancers, splice sites, and termination signals. Elevated transcript expression of the endogenous retrovirus group HERV-K (HML-2) is seen in many human cancers, although the identity of the individual proviral loci contributing to this expression as well as their mechanism of activation has been unclear. Using high-throughput next-generation sequencing techniques optimized for the capture of HML-2 expression, we characterized the HML-2 transcriptome and means of activation in an in vitro model of human mammary epithelial cell transformation. Our analysis showed significant expression originating from fifteen HML-2 full-length proviruses, through four modes of transcription. The majority of expression was in antisense orientation and from proviruses integrated within introns. We found two instances of LTR-driven provirus transcription but no evidence to suggest that these active 5' LTRs were influencing nearby host gene expression. Importantly, LTR-driven transcription was restricted to tumorigenic cells, suggesting that LTR promoter activity is dependent upon the transcriptional environment of a malignant cell.IMPORTANCE Here, we use an in vitro model of human mammary epithelial cell transformation to assess how malignancy-associated shifts in the transcriptional milieu of a cell may impact HML-2 activity. We found fifteen proviruses to be significantly expressed through four different mechanisms, with the majority of transcripts being antisense copies of proviruses located within introns. We saw active 5' LTR use in tumorigenic cells only, suggesting that the cellular environment of a cancer cell is a critical component for induction of LTR promoter activity. These findings have implications for future studies investigating HML-2 as a target for immunotherapy or as a biomarker for disease.

Publisher URL: http://doi.org/10.1128/JVI.01258-17

DOI: 10.1128/JVI.01258-17

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