GEO series
Targeting CDK7 function in the RNA Polymerase II transcription cycle in inflammatory arthritis
GSE255108
Mus musculus; Homo sapiens
Expression profiling by high throughput sequencing
64 samples
Submitted 2025/01/29
Platform GPL18573Platform GPL24676Platform GPL34281Platform GPL30173Platform GPL24247
Summary
Macrophages are main drivers of inflammation and tissue damage in autoimmune diseases including rheumatoid arthritis1-4. The rate-limiting step for transcription of >70% of inducible genes in macrophages is RNA Polymerase II (Pol II) promoter-proximal pause release5-7, yet, the specific role of Pol II pausing in inflammation or whether it can be modulated therapeutically is unknown. Genetic ablation of a pause-stabilizing negative elongation factor (NELF) in macrophages enhanced the transcriptional response of paused anti-inflammatory genes to LPS, followed by secondary attenuation of inflammatory signaling, and reduced severity of K/BxN-serum transfer (ST) arthritis in mice. To disrupt Pol II pause establishment pharmacologically, we employed covalent inhibitors of the TFIIH-associated cyclin-dependent kinase (CDK) 7, THZ1 and YKL-5-124. Both dramatically reduced Pol II pausing in murine and human macrophages, broadly suppressed induction of pro- but not anti-inflammatory genes, and rapidly reversed pre-established inflammatory macrophage polarization by TNF+IFNγ. In vivo, CDK7i ameliorated the acute K/BxN-ST and chronic progressive hTNF-transgenic arthritis in mice. Finally, CDK7i downregulated a pathogenic gene expression signature in synovial explants from arthritis patients. We propose that interfering with Pol II pausing by targeting CDK7 represents a novel therapeutic opportunity for inflammatory diseases.
Published in
Chen X, Shibu G, Sokolsky BA et al.
· Science translational medicine 2024
· PMID 39565872
· doi:10.1126/scitranslmed.adq5091
This dataset
Download
Direct links to NCBI, no account and no request form: the whole study as GSE255108_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 64 samples. Raw sequencing reads are also available from ENA.
Also filed as BioProject PRJNA1073533 and SRA study SRP488247. Searching any of these in the dataset finder brings you back here.
Study design
15 conditions, mostly in triplicate
DMSO_0h ×3
LPS_1h ×3
LPS_6h ×3
LPS_12h ×3
YKL_0h ×3
YKL_LPS_1h ×3
YKL_LPS_6h ×3
YKL_LPS_12h ×3
+9 more
Supports a between-group comparison across 38 samples.
15 replicated groups read from the first 40 of 64 sample titles; they account for 38 of them. Check it against the sample list below before relying on it.
Samples in this study
0 selected
- GSM8064230 DMSO_0h_Rep1
- GSM8064231 LPS_1h_Rep1
- GSM8064232 LPS_6h_Rep1
- GSM8064233 LPS_12h_Rep1
- GSM8064234 YKL_0h_Rep1
- GSM8064235 YKL_LPS_1h_Rep1
- GSM8064236 YKL_LPS_6h_Rep1
- GSM8064237 YKL_LPS_12h_Rep1
- GSM8064238 DMSO_0h_Rep2
- GSM8064239 LPS_1h_Rep2
- GSM8064240 LPS_6h_Rep2
- GSM8064241 LPS_12h_Rep2
- GSM8064242 YKL_0h_Rep2
- GSM8064243 YKL_LPS_1h_Rep2
- GSM8064244 YKL_LPS_6h_Rep2
- GSM8064245 YKL_LPS_12h_Rep2
- GSM8064246 DMSO_0h_Rep3
- GSM8064247 LPS_1h_Rep3
- GSM8064248 LPS_6h_Rep3
- GSM8064249 LPS_12h_Rep3
- GSM8064250 YKL_0h_Rep3
- GSM8064251 YKL_LPS_1h_Rep3
- GSM8064252 YKL_LPS_6h_Rep3
- GSM8064253 YKL_LPS_12h_Rep3
- GSM8064254 vehicle_B2_rep1
- GSM8064255 TNFa_IFNg_24h_B2_rep1
- GSM8064256 TNFa_IFNg_YKL_24h_3h_B2_rep1
- GSM8064257 TNFa_IFNg_YKL_24h_6h_B2_rep1
- GSM8064258 vehicle_B1_rep2
- GSM8064259 TNFa_IFNg_24h_B1_rep2
- GSM8064260 TNFa_IFNg_YKL_24h_3h_B1_rep2
- GSM8064261 TNFa_IFNg_YKL_24h_6h_B1_rep2
- GSM8064262 vehicle_B1_rep3
- GSM8064263 TNFa_IFNg_24h_B3_rep3
- GSM8064264 TNFa_IFNg_YKL_24h_3h_B1_rep3
- GSM8064265 TNFa_IFNg_YKL_24h_6h_B1_rep3
- GSM8064266 vehicle_B2_rep4
- GSM8064267 TNFa_IFNg_24h_B2_rep4
- GSM8064268 TNFa_IFNg_YKL_24h_3h_B2_rep4
- GSM8064269 TNFa_IFNg_YKL_24h_6h_B2_rep4
+ 24 more — browse all 64 samples with per-sample file links →
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