TET3 is a common epigenetic immunomodulator of pathogenic macrophages
Beibei Liu, Yangyang Dai, Zixin Wang, Jiahui Song, Yushu Du, Haining Lv, Stefania Bellone, Yang-Hartwich Yang, Andrew Kennedy, Songying Zhang, Muthukumaran Venkatachalapathy, Yulia Surovtseva, Penghua Wang, Gordon G. Carmichael, Hugh S. Taylor, Xuchen Zhang, Da Li, Yingqun Huang
Beibei Liu, Yangyang Dai, Zixin Wang, Jiahui Song, Yushu Du, Haining Lv, Stefania Bellone, Yang-Hartwich Yang, Andrew Kennedy, Songying Zhang, Muthukumaran Venkatachalapathy, Yulia Surovtseva, Penghua Wang, Gordon G. Carmichael, Hugh S. Taylor, Xuchen Zhang, Da Li, Yingqun Huang
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Research Article Hepatology Immunology Inflammation

TET3 is a common epigenetic immunomodulator of pathogenic macrophages

Abstract

Through a combination of single-cell/single-nucleus RNA-Seq (sc/snRNA-Seq) data analysis, immunohistochemistry, and primary macrophage studies, we have identified pathogenic macrophages characterized by Tet methylcytosine dioxygenase 3 (TET3) overexpression (Toe-Macs) in 3 major human diseases associated with chronic inflammation: metabolic dysfunction–associated steatohepatitis (MASH), non–small cell lung cancer (NSCLC), and endometriosis. These macrophages are induced by common factors present in the disease microenvironment (DME). Crucially, the universal reliance on TET3 overexpression among these macrophages enabled their selective elimination as a single population, irrespective of heterogeneity in other molecular markers. In mice, depleting these macrophages via myeloid-specific Tet3 KO markedly mitigated disease progression, and the therapeutic effects were recapitulated pharmacologically using a TET3-specific small-molecule degrader. Through an unexpected mode of action, TET3 epigenetically regulated the expression of multiple genes key to the generation and maintenance of an inflammatory/immunosuppressive DME. We propose that Toe-Macs are a unifying feature of pathogenic macrophages that could be therapeutically targeted to treat MASH, NSCLC, endometriosis, and potentially other chronic inflammatory diseases.

Authors

Beibei Liu, Yangyang Dai, Zixin Wang, Jiahui Song, Yushu Du, Haining Lv, Stefania Bellone, Yang-Hartwich Yang, Andrew Kennedy, Songying Zhang, Muthukumaran Venkatachalapathy, Yulia Surovtseva, Penghua Wang, Gordon G. Carmichael, Hugh S. Taylor, Xuchen Zhang, Da Li, Yingqun Huang

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Figure 4

Bc destabilizes TET3 protein through enhancing a ternary complex formation with VHL.

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Bc destabilizes TET3 protein through enhancing a ternary complex formati...
(A) Co-IP of Flag-TET3 and endogenous VHL in MDMs infected with Ad-TET3 (which expresses a Flag-tagged human TET3), with or without the presence of Bc, at 50 μM for 2 hours. (B) AlphaScreen of dose-response curves of Bc at different concentrations (conc) for binding of TET3, TET2, and TET1 to VHL. (C) Western blots of TET3, TET2, and TET1 in MDMs incubated for 24 hours or 48 hours with Veh or Bc at a final concentration of 10 μM. (D) MDMs were incubated for 2 hours with Veh or Bc at a final concentration of 10 μM, followed by time-course analysis of TET3, TET2, and TET1 in the presence of cycloheximide (CHX) at a final concentration of 50 μg/mL. Cells were harvested at 0, 20, 40, and 60 minutes after addition of CHX. Quantifications are displayed on the right. Western blot data are representative of 2–3 biological repeats.