通过抑制 CDK7 破坏 RNA 聚合酶 II 转录周期可改善炎症性关节炎

IF 15.8 1区 医学 Q1 CELL BIOLOGY
Xi Chen, Gayathri Shibu, Baila A. Sokolsky, Tamar Nicole Soussana, Logan Fisher, Dinesh K. Deochand, Marija Dacic, Ian Mantel, Daniel C. Ramirez, Richard D. Bell, Tinghu Zhang, Laura T. Donlin, Susan M. Goodman, Nathanael S. Gray, Yurii Chinenov, Robert P. Fisher, Inez Rogatsky
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引用次数: 0

摘要

巨噬细胞是自身免疫性疾病(包括类风湿性关节炎)中炎症和组织损伤的主要驱动因素。巨噬细胞中70%以上的诱导基因转录的限速步骤是RNA聚合酶II(Pol II)启动子-近端暂停释放;然而,Pol II早期伸长控制在炎症中的具体作用以及是否能对其进行治疗调节尚不清楚。基因消减巨噬细胞中的暂停稳定负伸长因子(NELF)不会影响基线 Pol II 占有率,但会增强暂停抗炎基因对脂多糖的转录反应,继而在体外和 K/BxN 血清转移关节炎小鼠模型中减轻炎症信号传导。为了从药理学角度破坏 Pol II 转录周期,我们使用了转录因子 II H 相关细胞周期蛋白依赖性激酶 7 (CDK7) 的两种共价抑制剂 THZ1 和 YKL-5-124。这两种抑制剂都能减少小鼠和人类巨噬细胞中 Pol II 的暂停,广泛抑制促炎基因而非抗炎基因的诱导,并迅速逆转已形成的炎性巨噬细胞极化。在小鼠中,CDK7 抑制可改善急性和慢性进行性炎症性关节炎。最后,CDK7 抑制下调了类风湿性关节炎患者滑膜组织中致病基因的表达特征。我们认为,通过靶向 CDK7 干扰 Pol II 早期伸长是治疗类风湿性关节炎和其他炎症性疾病的一个机会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Disrupting 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 Pol II transcription cycle, we used two covalent inhibitors of the transcription factor II H-associated cyclin-dependent kinase 7 (CDK7), THZ1 and YKL-5-124. Both reduced Pol II pausing in murine and human macrophages, broadly suppressed induction of pro- but not anti-inflammatory genes, and rapidly reversed preestablished inflammatory macrophage polarization. In mice, CDK7 inhibition ameliorated both acute and chronic progressive inflammatory arthritis. Lastly, CDK7 inhibition down-regulated a pathogenic gene expression signature in synovial explants from patients with rheumatoid arthritis. We propose that interfering with Pol II early elongation by targeting CDK7 represents a therapeutic opportunity for rheumatoid arthritis and other inflammatory diseases.
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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