School of Biological Sciences, Department of Molecular Biology, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Microbiology, Immunity Theme, Biomedical Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
Immunity. 2023 May 9;56(5):959-978.e10. doi: 10.1016/j.immuni.2023.03.017. Epub 2023 Apr 10.
Although the importance of genome organization for transcriptional regulation of cell-fate decisions and function is clear, the changes in chromatin architecture and how these impact effector and memory CD8 T cell differentiation remain unknown. Using Hi-C, we studied how genome configuration is integrated with CD8 T cell differentiation during infection and investigated the role of CTCF, a key chromatin remodeler, in modulating CD8 T cell fates through CTCF knockdown approaches and perturbation of specific CTCF-binding sites. We observed subset-specific changes in chromatin organization and CTCF binding and revealed that weak-affinity CTCF binding promotes terminal differentiation of CD8 T cells through the regulation of transcriptional programs. Further, patients with de novo CTCF mutations had reduced expression of the terminal-effector genes in peripheral blood lymphocytes. Therefore, in addition to establishing genome architecture, CTCF regulates effector CD8 T cell heterogeneity through altering interactions that regulate the transcription factor landscape and transcriptome.
虽然基因组组织对于细胞命运决定和功能的转录调控的重要性是显而易见的，但染色质结构的变化以及这些变化如何影响效应器和记忆 CD8 T 细胞分化仍然未知。我们使用 Hi-C 技术研究了在感染过程中基因组构象如何与 CD8 T 细胞分化相整合，并通过 CTCF 敲低方法和特定 CTCF 结合位点的扰动研究了关键染色质重塑因子 CTCF 在调节 CD8 T 细胞命运中的作用。我们观察到染色质组织和 CTCF 结合的亚群特异性变化，并揭示了弱亲和力 CTCF 结合通过调节转录程序促进 CD8 T 细胞的终末分化。此外，患有从头 CTCF 突变的患者在外周血淋巴细胞中表达的终末效应基因减少。因此，除了建立基因组结构外，CTCF 通过改变调节转录因子景观和转录组的相互作用来调节效应器 CD8 T 细胞异质性。
