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

Pan Jia,Yingying Xu,Liangjiao Yao,Yu Hu,Xuelei Wang,Meiyu Zhang,Yi Zang,Wei Lu,Yan Zhang,Zhe He,Qifan Zhao,Wenwen Xu,Jun Qin,Xiang Li,Yicong Deng

doi:10.1038/s41467-021-26864-x

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.

Highlights

Super-enhancers (SEs) govern macrophage polarization and function
Our results suggest that ZMYND8 is a vital gatekeeper for macrophage-mediated inflammation
The in vivo relevance of our findings was evident in mouse models of colitis and obesity, which resulted in the aggravated disease upon conditional ablation of Zmynd[8] in macrophages

Summary

Introduction

Super-enhancers (SEs) govern macrophage polarization and function. the mechanism underlying the signal-dependent latent SEs remodeling in macrophages remains largely undefined. Some massive clusters of cis-regulatory elements characterized by longer stretches of DNA, a higher level of histone H3K27 acetylation were defined as super-enhancers (SEs)[7,8] They are bound with large amounts of transcription factors (TF) and coactivators to drive lineage-specific gene expression[9,10,11]. It has been illuminated that various extracellular stimuli prime and activate the subset-specific SE profile in macrophages[28] How those enhancers, especially latent SEs being silenced or fine-tuned to control the magnitude of the macrophage-mediated immune response, is still unclear. Dependent on its liquidity feature, ZMYND8 compartments undergo dynamic translocation onto NF-κB associated latent SEs and suppress the subsequent pro-inflammatory genes expression through LSD1mediated enhancer deactivation. The epigenetic reader coalesces with post-translationally modified TFs to increase the regulatory specificity and efficiency on SEs-related gene transcription

Methods

Results

Conclusion