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bioRxiv · 10.1101/2025.03.09.642286

A tumor necrosis factor-α responsive cryptic promoter drives overexpression of the human endogenous retrovirus ERVK-7

LEE, S.·Ho, Y. Y.·Hao, S.·Ouyang, Y.·Liew, U. L.·Goyal, A.·Li, S.·Barbour, J. A.·He, M.·Huang, Y.·Wong, J. W. H.
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Abstract

Endogenous retroviruses (ERVs) shape human genome functionality and influence disease pathogenesis, including cancer. ERVK-7, a significant ERV, acts as an immune modulator and prognostic marker in lung adenocarcinoma (LUAD). Although ERVK-7 overexpression has been linked to the amplification of the 1q22 locus in approximately 10% of LUAD cases, it predominantly arises from alternative regulatory mechanisms. Our findings indicate that the canonical 5 long terminal repeat (LTR) of ERVK-7 is methylated and inactive, necessitating the use of alternative upstream promoters. We identified two novel transcripts, ERVK-7.long and ERVK-7.short, arising from distinct promoters located 2.8 kb and 13.8 kb upstream of the 5LTR of ERVK-7, respectively. ERVK-7.long is predominantly overexpressed in LUAD. Through comprehensive epigenetic mapping and single-cell transcriptomics, we demonstrate that ERVK-7.long activation is predetermined by cell lineage, specifically in small airway epithelial cells (SAECs), where its promoter displays tumor-specific H3K4me3 modifications. Single-cell RNA sequencing further reveals a distinct enrichment of ERVK-7.long in LUAD tumor cells and alveolar type 2 epithelial cells, underscoring a cell-type-specific origin. Additionally, inflammatory signaling significantly influences ERVK-7 expression; TNF- enhances ERVK-7.long, while interferon signaling preferentially augments ERVK-7.short by differential recruitment of NF-{kappa}B/RELA and IRF to their respective promoters. This differential regulation clarifies the elevated ERVK-7 expression in LUAD compared to lung squamous cell carcinoma (LUSC). Our study elucidates the complex regulatory mechanisms governing ERVK-7 in LUAD and proposes these transcripts as potential biomarkers and therapeutic targets, offering new avenues to improve patient outcomes.

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LEE, S., Ho, Y. Y., Hao, S., Ouyang, Y., Liew, U. L., Goyal, A., Li, S., Barbour, J. A., He, M., Huang, Y., Wong, J. W. H.. 2025-03-13. A tumor necrosis factor-α responsive cryptic promoter drives overexpression of the human endogenous retrovirus ERVK-7. https://doi.org/10.1101/2025.03.09.642286

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