p52:ETS1: a transcriptional complex essential for germinal center formation [RNA_Seq_preGCB]

It is well-established that the five transcription factors of the NFκB family form homo/hetero dimers amongst themselves to regulate gene expression by binding DNA. Our study challenges this paradigm by showing that p52 activates transcription without directly binding DNA but as part of a hetero-tetrameric partnership with ETS1, a transcription factor outside the NFκB family. By generating a knock-in mouse model (p52ki/ki) with three mutated residues on p52 required for its interactions with ETS1 but not with RelB, we demonstrate that the p52:ETS1 complex is the hitherto undiscovered regulator of transcription factors, OCT1 and OBF1, known to be critical for the germinal centre (GC) program. Consequently B cell-intrinsic expression of p52:ETS1 complex is indispensable for splenic GC B cell formation and T cell-dependent antibody responses. Functionally, loss of p52:ETS1 interaction led to diminished antigen-specific IgE thereby protecting mice from allergic responses. Collectively, our expand our current knowledge of NFkB signalling and provide new therapeutic targets for the treatment of allergic diseases. RNA-Seq profiling of WT and p52 knock-in mouse spleen pre-GC and GC B cells.

学界已达成共识：核因子κB（NFκB）家族的五种转录因子可通过彼此形成同源/异源二聚体并结合DNA，进而调控基因表达。本研究对此经典范式提出挑战：研究发现p52可在不直接结合DNA的情况下激活转录，而是作为异源四聚体复合物的一部分，与NFκB家族之外的ETS1转录因子相互作用。本研究构建了p52ki/ki敲入小鼠模型，该模型的p52蛋白上存在三个突变残基，这些残基是p52与ETS1结合所必需的，但不影响其与RelB的相互作用。研究证实，p52:ETS1复合物是迄今尚未被发现的转录因子OCT1与OBF1的调控因子，这两种转录因子对于生发中心（GC）程序至关重要。因此，p52:ETS1复合物在B细胞内的固有表达，对于脾脏生发中心B细胞的形成以及T细胞依赖性抗体应答是不可或缺的。功能层面上，p52与ETS1的相互作用缺失会导致抗原特异性IgE水平降低，从而使小鼠免受过敏反应的侵扰。综上，本研究拓展了我们对NFκB信号通路的现有认知，并为过敏性疾病的治疗提供了全新的治疗靶点。本数据集涵盖野生型（WT）与p52敲入小鼠脾脏前生发中心（pre-GC）及生发中心（GC）B细胞的RNA测序（RNA-Seq）谱型数据。