Hierarchical interactions between chromatin remodeling transcription factors define the epigenetic landscape of antiviral T cells. Hierarchical interactions between chromatin remodeling transcription factors define the epigenetic landscape of antiviral T cells

T cell activation induces rapid proliferative expansion and the acquisitions of specialized effector functions that enable protection against invading pathogens. While a multitude of transcription factors (TFs) have been implicated in the regulation of T cell activation, it remains largely unclear how their functions are organized and integrated at the genomic level. Here, we leveraged naturally occurring TF binding site polymorphisms in wild derived inbred mice to identify the most critical “heavy lifters” that shape the epigenetic landscape of naïve and activated antiviral CD4 and CD8 T cells. We found that representative members of Ets, Runx, and TCF/Lef families occupied the vast majority of accessible chromatin regions and that interactions between them were associated with distinct epigenetic responses to T cell activation. We define prevalent genomic functions of Ets1, Runx1, and TCF1 as “housekeeper”, “universal amplifier”, and “placeholder”, respectively. Interestingly, regulatory elements associated with some of the most strongly induced and well-characterized immune response genes showed a non-canonical pattern of TF recruitment. Overall design: The project studied the chromatin accessibility and multiple transcription factors binding profiles of CD8/CD4 T cell in response to virial infection. 84 samples were analysed in total, including 12 ATAC-Seq, 12 RNA-Seq, 60 CUT&RUN samples.

T细胞激活可诱导快速增殖扩增，并获得特化的效应功能，以抵御入侵的病原体。尽管已有大量转录因子（transcription factors, TFs）被证实参与调控T细胞激活过程，但目前在基因组层面上，这些转录因子的功能如何组织与整合仍尚未明确。本研究借助野生来源近交系小鼠中天然存在的转录因子结合位点多态性，筛选出塑造初始态与激活态抗病毒CD4、CD8 T细胞表观遗传景观的核心关键调控因子。我们发现，Ets、Runx及TCF/Lef家族的代表性转录因子占据了绝大多数染色质可及区域，且这些因子间的互作与T细胞激活后的特异性表观遗传应答密切相关。我们将Ets1、Runx1及TCF1的典型基因组功能分别定义为"管家因子"、"通用扩增因子"与"占位因子"。有趣的是，部分与诱导程度最强且研究最为透彻的免疫应答基因相关的调控元件，展现出非经典的转录因子招募模式。整体实验设计：本项目针对病毒感染应答过程中的CD4、CD8 T细胞，开展了染色质可及性与多种转录因子结合谱的研究。总计分析84例样本，其中包括12例ATAC测序（ATAC-Seq）、12例RNA测序（RNA-Seq）以及60例CUT&RUN测序（CUT&RUN）。