Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
Immunity. 2020 Dec 15;53(6):1151-1167.e6. doi: 10.1016/j.immuni.2020.10.009. Epub 2020 Nov 6.
Establishment of B-lineage-specific gene expression requires the binding of transcription factors to inaccessible chromatin of progenitors. The transcription factor EBF1 can bind genomic regions prior to the detection of chromatin accessibility in a manner dependent on EBF1's C-terminal domain (CTD) and independent of cooperating transcription factors. Here, we studied the mechanism whereby the CTD enables this pioneering function. The CTD of EBF1 was dispensable for initial chromatin targeting but stabilized occupancy via recruitment of the chromatin remodeler Brg1. We found that the CTD harbors a prion-like domain (PLD) with an ability of liquid-liquid phase separation, which was enhanced by interaction of EBF1 with the RNA-binding protein FUS. Brg1 also partitioned into phase-separated FUS condensates and coincided with EBF1 and FUS foci in pro-B cells. Heterologous PLDs conferred pioneering function on EBF1ΔCTD. Thus, the phase separation ability of EBF1 facilitates Brg1-mediated chromatin opening and the transition of naive progenitor chromatin to B-lineage-committed chromatin.
B 细胞谱系特异性基因表达的建立需要转录因子与祖细胞中不可及的染色质结合。转录因子 EBF1 可以在染色质可及性检测之前结合基因组区域，这种结合方式依赖于 EBF1 的 C 端结构域（CTD），而不依赖于合作转录因子。在这里，我们研究了 CTD 使这种开拓性功能成为可能的机制。EBF1 的 CTD 对于初始染色质靶向是可有可无的，但通过招募染色质重塑因子 Brg1 稳定了其占据。我们发现 CTD 具有类朊病毒结构域（PLD），具有液-液相分离的能力，而 EBF1 与 RNA 结合蛋白 FUS 的相互作用增强了这种能力。Brg1 也分配到相分离的 FUS 凝聚物中，并与前 B 细胞中的 EBF1 和 FUS 焦点重合。异源 PLD 赋予 EBF1ΔCTD 开拓性功能。因此，EBF1 的相分离能力促进了 Brg1 介导的染色质开放以及原始祖细胞染色质向 B 细胞谱系特异性染色质的转变。
