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000300774 1001_ $$aLee, Sojung$$b0
000300774 245__ $$aA tumour necrosis factor-α responsive cryptic promoter drives overexpression of the human endogenous retrovirus ERVK-7.
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000300774 520__ $$aEndogenous 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 5'LTR 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-α enhances ERVK-7.long, while interferon signaling preferentially augments ERVK-7.short by differential recruitment of NF-κB/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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000300774 7001_ $$aHo, Yin Yee$$b1
000300774 7001_ $$aHao, Suyu$$b2
000300774 7001_ $$aOuyang, Yingqi$$b3
000300774 7001_ $$aLiew, U Ling$$b4
000300774 7001_ $$0P:(DE-He78)be1522c665d3d9a98c00fc0f77a9bf0b$$aGoyal, Ashish$$b5$$udkfz
000300774 7001_ $$aLi, Stephen$$b6
000300774 7001_ $$aBarbour, Jayne A$$b7
000300774 7001_ $$aHe, Mu$$b8
000300774 7001_ $$aHuang, Yuanhua$$b9
000300774 7001_ $$aWong, Jason W H$$b10
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