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@ARTICLE{Lee:300774,
      author       = {S. Lee and Y. Y. Ho and S. Hao and Y. Ouyang and U. L. Liew
                      and A. Goyal$^*$ and S. Li and J. A. Barbour and M. He and
                      Y. Huang and J. W. H. Wong},
      title        = {{A} tumour necrosis factor-α responsive cryptic promoter
                      drives overexpression of the human endogenous retrovirus
                      {ERVK}-7.},
      journal      = {The journal of biological chemistry},
      volume       = {301},
      number       = {6},
      issn         = {0021-9258},
      address      = {Bethesda, Md.},
      publisher    = {Soc.},
      reportid     = {DKFZ-2025-00922},
      pages        = {108568},
      year         = {2025},
      note         = {Volume 301, Issue 6, June 2025, 108568},
      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 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.},
      cin          = {B370},
      ddc          = {540},
      cid          = {I:(DE-He78)B370-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40316021},
      doi          = {10.1016/j.jbc.2025.108568},
      url          = {https://inrepo02.dkfz.de/record/300774},
}