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<p>Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) are abundant viral noncoding RNAs that associate with host chromatin, but the promoter-scale consequences of those contacts remain unclear. We re-analyzed GSE281522 in EBV-positive GM12878 cells integrating RNA–DNA contacts, RNAPII ChIA-PET, RNA-seq and internal ATAC-seq after EBER depletion. Promoters were classified according to increased RNAPII-associated promoter-looping signal after EBER depletion relative to the matched control conditions, defined as LoopRecovery; increased transcriptional output, defined as ExprUp; or the coordinated occurrence of both responses, defined as Recovery + Up. EBER-contacted promoters were markedly depleted for Recovery + Up relative to non-contacted promoters (0.42% vs 2.00%; OR ~ 0.21; Fisher’s exact <i>p</i> ~ 6.3 × 10<sup>–5</sup>), and the association between increased promoter looping and transcriptional upregulation was attenuated among EBER-contacted promoters. This depletion remained directionally stable across alternative threshold grids, loop-support and expression filters, and promoter-window definitions using TSS-centered intervals of ± 1&#xa0;kb, ± 2&#xa0;kb and ± 5&#xa0;kb (ORs 0.416, 0.208 and 0.110, respectively). To test whether the constrained class simply reflected inactive chromatin, we integrated internal ATAC-seq from the same study. Constraint-core promoters, defined as EBER-contacted promoters that did not enter Recovery + Up, remained accessible, with ATAC overlap observed in 89.38% versus 68.38% of comparator promoters in any replicate and higher replicate-averaged ATAC signal (median 42.55 vs. 10.43). Ranked Hallmark enrichment and top-contact over-representation converged on TNFA_SIGNALING_VIA_NFKB as the strongest pathway-level signal, and candidate loci including RIPK2, IL15RA, ICAM1, TNFAIP3 and NFKBIA defined accessible but constrained promoter hubs. Control RNA contact maps did not reproduce a uniform EBER-like phenotype. Together, these analyses support a model in which EBER-associated contacts mark accessible yet transcriptionally constrained RNAPII promoter hubs in EBV-positive B cells.</p> Graphical Abstract <p></p>

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EBER-associated promoter contacts mark accessible but transcriptionally constrained RNAPII promoter hubs in EBV-positive B cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月20日

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  • Shaik Ismail Mohammed Thangameeran,
  • Hemalatha Mani,
  • Chih-Wen Peng

摘要

Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) are abundant viral noncoding RNAs that associate with host chromatin, but the promoter-scale consequences of those contacts remain unclear. We re-analyzed GSE281522 in EBV-positive GM12878 cells integrating RNA–DNA contacts, RNAPII ChIA-PET, RNA-seq and internal ATAC-seq after EBER depletion. Promoters were classified according to increased RNAPII-associated promoter-looping signal after EBER depletion relative to the matched control conditions, defined as LoopRecovery; increased transcriptional output, defined as ExprUp; or the coordinated occurrence of both responses, defined as Recovery + Up. EBER-contacted promoters were markedly depleted for Recovery + Up relative to non-contacted promoters (0.42% vs 2.00%; OR ~ 0.21; Fisher’s exact p ~ 6.3 × 10–5), and the association between increased promoter looping and transcriptional upregulation was attenuated among EBER-contacted promoters. This depletion remained directionally stable across alternative threshold grids, loop-support and expression filters, and promoter-window definitions using TSS-centered intervals of ± 1 kb, ± 2 kb and ± 5 kb (ORs 0.416, 0.208 and 0.110, respectively). To test whether the constrained class simply reflected inactive chromatin, we integrated internal ATAC-seq from the same study. Constraint-core promoters, defined as EBER-contacted promoters that did not enter Recovery + Up, remained accessible, with ATAC overlap observed in 89.38% versus 68.38% of comparator promoters in any replicate and higher replicate-averaged ATAC signal (median 42.55 vs. 10.43). Ranked Hallmark enrichment and top-contact over-representation converged on TNFA_SIGNALING_VIA_NFKB as the strongest pathway-level signal, and candidate loci including RIPK2, IL15RA, ICAM1, TNFAIP3 and NFKBIA defined accessible but constrained promoter hubs. Control RNA contact maps did not reproduce a uniform EBER-like phenotype. Together, these analyses support a model in which EBER-associated contacts mark accessible yet transcriptionally constrained RNAPII promoter hubs in EBV-positive B cells.

Graphical Abstract