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

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 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 and 13.8 kb upstream of the 5' long terminal repeat 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, where its promoter displays tumor-specific H3K4me3 modifications. Single-cell RNA-Seq 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. In addition, inflammatory signaling significantly influences ERVK-7 expression; tumor necrosis factor-α enhances ERVK-7.long, whereas interferon signaling preferentially augments ERVK-7.short by differential recruitment of NF-κB/RELA and interferon regulatory factor to their respective promoters. This differential regulation clarifies the elevated ERVK-7 expression in LUAD compared with lung squamous cell carcinoma. 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.