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Elevated WTAP promotes hyperinflammation by increasing m6A modification in inflammatory disease models
Yong Ge, … , Shaochun Yuan, Anlong Xu
Yong Ge, … , Shaochun Yuan, Anlong Xu
Published July 15, 2024
Citation Information: J Clin Invest. 2024;134(14):e177932. https://doi.org/10.1172/JCI177932.
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Research Article Immunology Inflammation Article has an altmetric score of 2

Elevated WTAP promotes hyperinflammation by increasing m6A modification in inflammatory disease models

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Abstract

Emerging evidence has linked the dysregulation of N6-methyladenosine (m6A) modification to inflammation and inflammatory diseases, but the underlying mechanism still needs investigation. Here, we found that high levels of m6A modification in a variety of hyperinflammatory states are p65-dependent because Wilms tumor 1–associated protein (WTAP), a key component of the “writer” complex, is transcriptionally regulated by p65, and its overexpression can lead to increased levels of m6A modification. Mechanistically, upregulated WTAP is more prone to phase separation to facilitate the aggregation of the writer complex to nuclear speckles and the deposition of m6A marks on transcriptionally active inflammatory transcripts, thereby accelerating the proinflammatory response. Further, a myeloid deficiency in WTAP attenuates the severity of LPS-induced sepsis and DSS-induced IBD. Thus, the proinflammatory effect of WTAP is a general risk-increasing mechanism, and interrupting the assembly of the m6A writer complex to reduce the global m6A levels by targeting the phase separation of WTAP may be a potential and promising therapeutic strategy for alleviating hyperinflammation.

Authors

Yong Ge, Rong Chen, Tao Ling, Biaodi Liu, Jingrong Huang, Youxiang Cheng, Yi Lin, Hongxuan Chen, Xiongmei Xie, Guomeng Xia, Guanzheng Luo, Shaochun Yuan, Anlong Xu

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Figure 8

Reducing the level of m6A modification can reverse the high inflammatory state.

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Reducing the level of m6A modification can reverse the high inflammatory...
(A and B) LC–MS/MS quantifying the m6A abundance (A) and heatmap showing the expression of proinflammatory genes (B) in HKST-stimulated BMDMs pretreated with DMSO or STM2457. (C and D) LC–MS/MS (C) and m6A dot blot (D) quantifying the m6A abundance in mRNA extracted from colon or lung tissues in septicemic mice pretreated with vehicle or STM2457. n = 3 mice. (E and F) qRT–PCR showing the mRNA abundance of proinflammatory genes in the colon (E) or lung (F) tissues from mice treated as above. n = 6 mice. (G) H&E assays showing the lung injury of LPS-induced sepsis of mice that treated as above. Scale bars: 50 μm. n = 3 mice. (H and I) Body weight changes (H) and disease activity index (I) of mice were monitored daily. n = 4 mice per group. (J and K) Macroscopic appearances (J) and colon lengths (K) of mice were recorded on day 8. n = 3 mice. (L) H&E assays showing the histopathological changes in colon tissue. Scale bars: 100 μm. n = 3 mice. (M) qRT–PCR showing the mRNA abundance of proinflammatory genes in the colon tissues from IBD mice intraperitoneally injected with vehicle or SC144. n = 8 mice. (N) LC–MS/MS quantification of m6A levels in mRNA extracted from LPS-stimulated THP-1 cells that pretreated with DMSO or PG490. Data are representative of 3 independent biological experiments in D, G, and J. Data are presented as the mean ± SD in A, C, E, F, K, M, and N, with individual measurements overlaid as dots. Statistical analysis was performed using 1-way ANOVA multiple comparisons in A and C or 2-tailed Student’s t test in E, F, K, M, and N.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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