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bioRxiv · 10.64898/2026.07.13.738346

Promoter-associated RNA polymerase III shapes RNA polymerase II-dependent inflammatory gene expression during viral infection

Lari, A.·Shah, S. B.·Batarseh, S.·Nagorsen, M.·Glaunsinger, B. A.
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Abstract

Cells must be primed to rapidly induce inflammatory gene expression upon infection while also tuning the level of induction to avoid immunopathology. Here, we identify RNA polymerase III (Pol III), best known for transcribing noncoding RNAs, as a dual-function regulator of RNA polymerase II (Pol II)-dependent inflammatory gene expression. Pol III is selectively enriched at promoters of innate immune, pro-inflammatory, and stress-response genes, where it maintains chromatin accessibility and supports basal transcription. Upon infection with murine gammaher-pesvirus 68 (MHV68), Pol III redistributes from these promoters to retrotransposon loci, coinciding with enhanced expression of inflammatory genes. Depletion of the Pol III transcription factor Brf1 further amplifies inflammatory transcription during infection with MHV68, herpes simplex virus-1, and influenza A virus. Genes restrained by Pol III have TATA-box-enriched promoters and are functionally dependent on TATA-binding protein (TBP), suggesting that Pol III modulates inflammatory gene expression by competing with Pol II for shared transcriptional machinery. Thus, Pol III is a chromatin licensor in uninfected cells and an inflammation rheostat during viral infection. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/738346v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@14e9026org.highwire.dtl.DTLVardef@d9bccborg.highwire.dtl.DTLVardef@f9d5b6org.highwire.dtl.DTLVardef@3dd384_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Lari, A., Shah, S. B., Batarseh, S., Nagorsen, M., Glaunsinger, B. A.. 2026-07-15. Promoter-associated RNA polymerase III shapes RNA polymerase II-dependent inflammatory gene expression during viral infection. https://doi.org/10.64898/2026.07.13.738346

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