A Prion-like Domain in Transcription Factor EBF1 Promotes Phase Separation and Enables B Cell Programming of Progenitor Chromatin

• Published in: Immunity (Cambridge, Mass.) Vol. 53; no. 6; pp. 1151 - 1167.e6
• Main Authors: Wang, Yuanting, Zolotarev, Nikolay, Yang, Cheng-Yuan, Rambold, Angelika, Mittler, Gerhard, Grosschedl, Rudolf
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.12.2020; Elsevier Limited
• Subjects: Binding sites; Brg1; BRG1 protein; Chromatin; Domains; EBF1; EWSR1; FUS; FUS protein; Gene expression; Liquid phases; Lymphocytes B; Occupancy; Phase separation; pioneer transcription factor; Proteins; Recruitment; Ribonucleic acid; RNA; RNA-binding protein; Transcription factors; phase separation; Brg1; pioneer transcription factor; FUS; EWSR1; EBF1; chromatin
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2020.10.009

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. [Display omitted] •B lineage chromatin pioneering by EBF1 requires a prion-like domain (PLD)•PLD stabilizes chromatin binding of EBF1 via Brg1 recruitment•EBF1 undergoes phase separation enhanced by interaction with FUS•Brg1 partitions into phase-separated FUS condensates Lineage-specific programming of chromatin requires transcription factors to bind inaccessible chromatin. Wang et al. find that “pioneering” by the transcription factor EBF1 involves a prion-like domain that enables recruitment of chromatin remodelers and formation of phase-separated condensates. Partitioning of EBF1-bound sites into condensates may coordinate expression of B lineage genes.