ZMYND8 mediated liquid condensates spatiotemporally decommission the latent super-enhancers during macrophage polarization

Pan Jia, Xiang Li, Xuelei Wang, Liangjiao Yao, Yingying Xu, Yu Hu, Wenwen Xu, Zhe He, Qifan Zhao, Yicong Deng, Yi Zang, Meiyu Zhang, Yan Zhang (), Jun Qin () and Wei Lu ()
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Pan Jia: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Xiang Li: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Xuelei Wang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Liangjiao Yao: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Yingying Xu: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Yu Hu: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Wenwen Xu: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Zhe He: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Qifan Zhao: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Yicong Deng: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Yi Zang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Meiyu Zhang: Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University School of Medicine
Yan Zhang: Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University School of Medicine
Jun Qin: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Wei Lu: University of Chinese Academy of Sciences, Chinese Academy of Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Super-enhancers (SEs) govern macrophage polarization and function. However, the mechanism underlying the signal-dependent latent SEs remodeling in macrophages remains largely undefined. Here we show that the epigenetic reader ZMYND8 forms liquid compartments with NF-κB/p65 to silence latent SEs and restrict macrophage-mediated inflammation. Mechanistically, the fusion of ZMYND8 and p65 liquid condensates is reinforced by signal-induced acetylation of p65. Then acetylated p65 guides the ZMYND8 redistribution onto latent SEs de novo generated in polarized macrophages, and consequently, recruit LSD1 to decommission latent SEs. The liquidity characteristic of ZMYND8 is critical for its regulatory effect since mutations coagulating ZMYND8 into solid compartments disable the translocation of ZMYND8 and its suppressive function. Thereby, ZMYND8 serves as a molecular rheostat to switch off latent SEs and control the magnitude of the immune response. Meanwhile, we propose a phase separation model by which the latent SEs are fine-tuned in a spatiotemporal manner.

Date: 2021
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DOI: 10.1038/s41467-021-26864-x

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