CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
Nat Commun. 2021 Nov 11;12(1):6535. doi: 10.1038/s41467-021-26864-x.
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.
超级增强子 (SEs) 调控巨噬细胞极化和功能。然而，信号依赖性潜伏 SEs 在巨噬细胞中的重塑机制在很大程度上仍未确定。在这里，我们表明表观遗传阅读器 ZMYND8 与 NF-κB/p65 形成液滴，以沉默潜伏 SEs 并限制巨噬细胞介导的炎症。在机制上，信号诱导的 p65 乙酰化增强了 ZMYND8 和 p65 液滴的融合。然后，乙酰化的 p65 引导 ZMYND8 重新分布到极化巨噬细胞中新生成的潜伏 SEs 上，并因此招募 LSD1 来撤销潜伏 SEs。ZMYND8 的流动性特征对于其调节作用至关重要，因为将 ZMYND8 凝聚成固体隔室的突变会使 ZMYND8 的易位和抑制功能失效。因此，ZMYND8 作为分子变阻器，可关闭潜伏 SEs 并控制免疫反应的强度。同时，我们提出了一个相分离模型，通过该模型可以在时空上精细调节潜伏 SEs。
