Chromatin organizer SATB1 controls the cell identity of CD4+ CD8+ double-positive thymocytes by regulating the activity of super-enhancers

Delong Feng, Yanhong Chen, Ranran Dai, Shasha Bian, Wei Xue, Yongchang Zhu, Zhaoqiang Li, Yiting Yang, Yan Zhang, Jiarui Zhang, Jie Bai, Litao Qin, Yoshinori Kohwi, Weili Shi, Terumi Kohwi-Shigematsu, Jing Ma, Shixiu Liao () and Bingtao Hao ()
Additional contact information
Delong Feng: Southern Medical University
Yanhong Chen: People’s Hospital of Zhengzhou University, Zhengzhou university
Ranran Dai: Southern Medical University
Shasha Bian: People’s Hospital of Zhengzhou University, Zhengzhou university
Wei Xue: Southern Medical University
Yongchang Zhu: People’s Hospital of Zhengzhou University, Zhengzhou university
Zhaoqiang Li: Southern Medical University
Yiting Yang: Southern Medical University
Yan Zhang: Southern Medical University
Jiarui Zhang: Southern Medical University
Jie Bai: People’s Hospital of Zhengzhou University, Zhengzhou university
Litao Qin: People’s Hospital of Zhengzhou University, Zhengzhou university
Yoshinori Kohwi: University of California, San Francisco
Weili Shi: People’s Hospital of Zhengzhou University, Zhengzhou university
Terumi Kohwi-Shigematsu: University of California, San Francisco
Jing Ma: Fudan University
Shixiu Liao: People’s Hospital of Zhengzhou University, Zhengzhou university
Bingtao Hao: Southern Medical University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract CD4+ and CD8+ double-positive (DP) thymocytes play a crucial role in T cell development in the thymus. DP cells rearrange the T cell receptor gene Tcra to generate T cell receptors with TCRβ. DP cells differentiate into CD4 or CD8 single-positive (SP) thymocytes, regulatory T cells, or invariant nature kill T cells (iNKT) in response to TCR signaling. Chromatin organizer SATB1 is highly expressed in DP cells and is essential in regulating Tcra rearrangement and differentiation of DP cells. Here we explored the mechanism of SATB1 orchestrating gene expression in DP cells. Single-cell RNA sequencing shows that Satb1 deletion changes the cell identity of DP thymocytes and down-regulates genes specifically and highly expressed in DP cells. Super-enhancers regulate the expressions of DP-specific genes, and our Hi-C data show that SATB1 deficiency in thymocytes reduces super-enhancer activity by specifically decreasing interactions among super-enhancers and between super-enhancers and promoters. Our results reveal that SATB1 plays a critical role in thymocyte development to promote the establishment of DP cell identity by globally regulating super-enhancers of DP cells at the chromatin architectural level.

Date: 2022
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DOI: 10.1038/s41467-022-33333-6

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