Identification of a novel enhancer essential for Satb1 expression in T_H2 cells and activated ILC2s

The genome organizer, special AT-rich binding protein-1 (SATB1), functions to globally regulate gene networks during primary T cell development and plays a pivotal role in lineage specification in CD4⁺ helper-, CD8⁺ cytotoxic-, and FOXP3⁺ regulatory-T cell subsets. However, it remains unclear how Satb1 gene expression is controlled, particularly in effector T cell function. Here, by using a novel reporter mouse strain expressing SATB1-Venus and genome editing, we have identified a cis-regulatory enhancer, essential for maintaining Satb1 expression specifically in T_H2 cells. This enhancer is occupied by STAT6 and interacts with Satb1 promoters through chromatin looping in T_H2 cells. Reduction of Satb1 expression, by the lack of this enhancer, resulted in elevated IL-5 expression in T_H2 cells. In addition, we found that Satb1 is induced in activated group 2 innate lymphoid cells (ILC2s) through this enhancer. Collectively, these results provide novel insights into how Satb1 expression is regulated in T_H2 cells and ILC2s during type 2 immune responses.