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

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

Nature communications (2021-11-13)
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, Wei Lu
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
ANTI-FLAG® M2 antibody, Mouse monoclonal, Clone M2, purified from hybridoma cell culture in bioreactor
Sigma-Aldrich
Anti-ZMYND8 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution