biostudies-literatureChen XNIDDK NIH HHSNIAID NIH HHSNCI NIH HHSNIAMS NIH HHSNIGMS NIH HHSeadq5091https://www.ebi.ac.uk/biostudies/studies/S-EPMC11756345biostudies-literatureUnknown16(774)Macrophages are key drivers of inflammation and tissue damage in autoimmune diseases including rheumatoid arthritis. The rate-limiting step for transcription of more than 70% of inducible genes in macrophages is RNA polymerase II (Pol II) promoter-proximal pause release; however, the specific role of Pol II early elongation control in inflammation, and whether it can be modulated therapeutically, is unknown. Genetic ablation of a pause-stabilizing negative elongation factor (NELF) in macrophages did not affect baseline Pol II occupancy but enhanced the transcriptional response of paused anti-inflammatory genes to lipopolysaccharide followed by secondary attenuation of inflammatory signaling in vitro and in the K/BxN serum transfer mouse model of arthritis. To pharmacologically disrupt the Science translational medicineDisrupting the RNA polymerase II transcription cycle through CDK7 inhibition ameliorates inflammatory arthritis.PMC11756345R01 AI148129R01 CA258553R01 AI148435UC2 AR081025R35 GM127289R01 DK099087Deochand DKFisher RPSoussana TNRogatsky IRamirez DCZhang TGray NSMantel IFisher LBell RDDonlin LTGoodman SMChinenov YChen XShibu GSokolsky BADacic MfalseDisrupting the RNA polymerase II transcription cycle through CDK7 inhibition ameliorates inflammatory arthritis.Macrophages are key drivers of inflammation and tissue damage in autoimmune diseases including rheumatoid arthritis. The rate-limiting step for transcription of more than 70% of inducible genes in macrophages is RNA polymerase II (Pol II) promoter-proximal pause release; however, the specific role of Pol II early elongation control in inflammation, and whether it can be modulated therapeutically, is unknown. Genetic ablation of a pause-stabilizing negative elongation factor (NELF) in macrophages did not affect baseline Pol II occupancy but enhanced the transcriptional response of paused anti-inflammatory genes to lipopolysaccharide followed by secondary attenuation of inflammatory signaling in vitro and in the K/BxN serum transfer mouse model of arthritis. To pharmacologically disrupt the 2024-01-01T00:00:00Z2024 Nov2026-06-11T04:53:37.812Z2026-06-11T03:07:55.434ZS-EPMC117563453956587210.1126/scitranslmed.adq5091