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

• Published in: Nature communications 2022-09, Vol.13 (1), p.5554-5554, Article 5554
• Main Authors: Feng, Delong, Chen, Yanhong, Dai, Ranran, Bian, Shasha, Xue, Wei, Zhu, Yongchang, Li, Zhaoqiang, Yang, Yiting, Zhang, Yan, Zhang, Jiarui, Bai, Jie, Qin, Litao, Kohwi, Yoshinori, Shi, Weili, Kohwi-Shigematsu, Terumi, Ma, Jing, Liao, Shixiu, Hao, Bingtao
• Format: Article
• Language: English
• Subjects: 38; 38/15; 38/39; 45; 45/91; 631/250/1619/554; 631/250/2502/2170; 631/337/100; CD4 antigen; CD8 antigen; Cell differentiation; Chromatin; Clonal deletion; Enhancers; Gene deletion; Gene expression; Gene sequencing; Genes; Genomes; Humanities and Social Sciences; Immunoregulation; Lymphocytes; Lymphocytes T; multidisciplinary; Receptors; Science; Science (multidisciplinary); T cell receptors; Thymocytes
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-33333-6

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. Here the authors show the identity of CD4 + CD8 + double-positive (DP) thymocytes changes upon loss of chromatin organizer Satb1, which controls the expression of cell identity genes by regulating super-enhancers via 3D genome architecture.