Identification of a novel enhancer essential for Satb1 expression in T(H)2 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(H)2 cells. This enhancer is occupied by STAT6 and interacts with Satb1 promoters through chromatin looping in T(H)2 cells. Reduction of Satb1 expression, by the lack of this enhancer, resulted in elevated IL-5 expression in T(H)2 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(H)2 cells and ILC2s during type 2 immune responses.