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Disrupting the RNA polymerase II transcription cycle through CDK7 inhibition ameliorates inflammatory arthritis

Xi Chen1,2, Gayathri Shibu1,2, Baila A Sokolsky1,2

  • 1Research Institute, Hospital for Special Surgery, New York, NY 10021, USA.

Science Translational Medicine
|November 20, 2024
PubMed

Insights

Targeting RNA polymerase II (Pol II) early elongation via CDK7 inhibition suppresses pro-inflammatory gene induction in macrophages. This approach shows therapeutic potential for rheumatoid arthritis and other inflammatory diseases.

Area of Science:

  • Immunology
  • Molecular Biology
  • Transcription Regulation

Background:

  • Macrophages are central to inflammation and tissue damage in autoimmune diseases like rheumatoid arthritis.
  • RNA polymerase II (Pol II) promoter-proximal pause release is a critical regulatory step for inducible gene transcription in macrophages.
  • The role of Pol II early elongation control in inflammation and its therapeutic potential remain largely unexplored.

Purpose of the Study:

  • To investigate the role of Pol II early elongation control in macrophage-driven inflammation.
  • To explore the therapeutic potential of modulating Pol II transcription by targeting cyclin-dependent kinase 7 (CDK7).

Main Methods:

  • Genetic ablation of the negative elongation factor (NELF) in macrophages.
  • Pharmacological inhibition of CDK7 using THZ1 and YKL-5-124 in murine and human macrophages.
  • Assessment of Pol II occupancy, gene transcription, and inflammatory signaling in vitro.
  • Evaluation of therapeutic efficacy in the K/BxN serum transfer mouse model of arthritis and synovial explants from rheumatoid arthritis patients.

Main Results:

  • Genetic ablation of NELF enhanced anti-inflammatory gene responses and attenuated inflammatory signaling.
  • CDK7 inhibition reduced Pol II pausing, suppressed pro-inflammatory gene induction, and reversed macrophage polarization.
  • CDK7 inhibition ameliorated acute and chronic inflammatory arthritis in mice.
  • CDK7 inhibition down-regulated a pathogenic gene signature in rheumatoid arthritis synovial explants.

Conclusions:

  • Targeting CDK7 to disrupt Pol II early elongation offers a novel therapeutic strategy for rheumatoid arthritis.
  • Modulating Pol II transcription by inhibiting CDK7 may be effective for treating various inflammatory diseases.

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