PU.1 and BCL11B sequentially cooperate with RUNX1 to anchor mSWI/SNF to poise the T cell effector landscape [CUT&RUN]

T cells trigger non-specific signaling pathways to elicit specialized effector functions to eliminate pathogens and cancers. Chromatin accessibility at T effector loci prior to antigen encounter poises cells to couple antigen recognition to the activation of lineage-specific responses. Here, by tracing the chromatin accessibility profiles unique to T effector functions during development, we find that the majority of T effector loci become accessible prior to antigen receptor expression. Epigenomic feature analysis, biochemical studies, and inducible perturbations identified two mechanistic linchpins: the physical association of the mSWI/SNF remodeling complex to the pleiotropic transcription factor (TF) RUNX1, and the cooperativity between RUNX1 and lineage-defining TFs PU.1 and BCL11B that respectively facilitate the establishment and maintenance of chromatin accessibility at T effector loci in early thymocyte progenitors. These findings reflect a design principle that allows distinct cell types to use the same signaling pathways to execute disparate roles which collectively orchestrate the immune response. CUT&RUN for BAF155 in wild type and Bcl11b cKO murine thymocytes.

T细胞可触发非特异性信号通路，以激活特异性效应功能，从而清除病原体与恶性肿瘤。在抗原识别前，T细胞效应基因座的染色质可及性可使细胞做好准备，将抗原识别与谱系特异性应答的激活相耦联。本研究通过追踪发育过程中T细胞效应功能所特有的染色质可及性图谱，发现绝大多数T细胞效应基因座在抗原受体表达前即已获得可及性。通过表观基因组特征分析、生化实验与诱导性扰动实验，本研究鉴定出两个核心机制枢纽：mSWI/SNF染色质重塑复合物与多效性转录因子（transcription factor, TF）RUNX1的物理结合，以及RUNX1与谱系决定性转录因子PU.1、BCL11B之间的协同作用——二者分别促进早期胸腺细胞祖细胞中T细胞效应基因座染色质可及性的建立与维持。上述发现揭示了一种设计原则：不同细胞类型可利用相同的信号通路执行差异化功能，共同协调机体免疫应答。本数据集包含野生型与Bcl11b条件性敲除（cKO）小鼠胸腺细胞中BAF155的CUT&RUN实验数据。