Tcf1 and Lef1 provide constant supervision to mature CD8+ T cell identity and function by organizing genomic architecture

Qiang Shan, Xiang Li, Xia Chen, Zhouhao Zeng, Shaoqi Zhu, Kexin Gai, Weiqun Peng () and Hai-Hui Xue ()
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Qiang Shan: Hackensack University Medical Center
Xiang Li: The George Washington University
Xia Chen: Capital Medical University
Zhouhao Zeng: The George Washington University
Shaoqi Zhu: The George Washington University
Kexin Gai: Hackensack University Medical Center
Weiqun Peng: The George Washington University
Hai-Hui Xue: Hackensack University Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract T cell identity is established during thymic development, but how it is maintained in the periphery remains unknown. Here we show that ablating Tcf1 and Lef1 transcription factors in mature CD8+ T cells aberrantly induces genes from non-T cell lineages. Using high-throughput chromosome-conformation-capture sequencing, we demonstrate that Tcf1/Lef1 are important for maintaining three-dimensional genome organization at multiple scales in CD8+ T cells. Comprehensive network analyses coupled with genome-wide profiling of chromatin accessibility and Tcf1 occupancy show the direct impact of Tcf1/Lef1 on the T cell genome is to promote formation of extensively interconnected hubs through enforcing chromatin interaction and accessibility. The integrative mechanisms utilized by Tcf1/Lef1 underlie activation of T cell identity genes and repression of non-T lineage genes, conferring fine control of various T cell functionalities. These findings suggest that Tcf1/Lef1 control global genome organization and help form intricate chromatin-interacting hubs to facilitate promoter-enhancer/silencer contact, hence providing constant supervision of CD8+ T cell identity and function.

Date: 2021
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DOI: 10.1038/s41467-021-26159-1

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