Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, La Jolla, CA, USA.
Biological Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA.
Nat Struct Mol Biol. 2019 Mar;26(3):193-203. doi: 10.1038/s41594-019-0190-5. Epub 2019 Mar 4.
A crucial feature of differentiated cells is the rapid activation of enhancer-driven transcriptional programs in response to signals. The potential contributions of physicochemical properties of enhancer assembly in signaling events remain poorly understood. Here we report that in human breast cancer cells, the acute 17β-estradiol-dependent activation of functional enhancers requires assembly of an enhancer RNA-dependent ribonucleoprotein (eRNP) complex exhibiting properties of phase-separated condensates. Unexpectedly, while acute ligand-dependent assembly of eRNPs resulted in enhancer activation sensitive to chemical disruption of phase separation, chronically activated enhancers proved resistant to such disruption, with progressive maturation of eRNPs to a more gel-like state. Acute, but not chronic, stimulation resulted in ligand-induced, condensin-dependent changes in spatial chromatin conformation based on homotypic enhancer association, resulting in cooperative enhancer-activation events. Thus, distinct physicochemical properties of eRNP condensates on enhancers serve as determinants of rapid ligand-dependent alterations in chromosomal architecture and cooperative enhancer activation.
分化细胞的一个关键特征是，它们能够快速激活增强子驱动的转录程序，以响应信号。然而，增强子组装的物理化学特性在信号事件中的潜在贡献仍知之甚少。在这里，我们报告在人类乳腺癌细胞中，功能性增强子的急性 17β-雌二醇依赖性激活需要组装具有相分离凝聚物特性的增强子 RNA 依赖性核糖核蛋白 (eRNP) 复合物。出乎意料的是，虽然急性配体依赖性 eRNP 的组装导致增强子激活对相分离化学破坏敏感，但慢性激活的增强子对这种破坏具有抗性，eRNP 逐渐成熟为更凝胶状的状态。急性刺激（而非慢性刺激）导致基于同源增强子关联的凝聚素依赖性空间染色质构象的配体诱导变化，从而导致协同增强子激活事件。因此，增强子上的 eRNP 凝聚物的不同物理化学特性可作为快速配体依赖性改变染色体结构和协同增强子激活的决定因素。
