SATB1 prevents immune cell infiltration by regulating chromatin organization and gene expression of a chemokine gene cluster in T cells [CUT&Tag]

Autoimmune diseases are systemic diseases caused by abnormalities of the immune system. Satb1 is a nuclear protein highly expressed in T cells and plays an important role in regulating the expression of T cell functional genes. However, its role in autoimmune diseases remains unclear. Our study found that conditional knockout of Satb1 in CD4+ T cells led to T cell hyperactivation and inflammatory cell infiltration in the lungs and stomach. By performing transcriptome profiling, we showed that the loss of SATB1 led to the aberrant upregulation of chemokines, particularly the ones belonging to the CC subfamily. We further found that SATB1 could bind to the promoters of CC chemokines and reduce the levels of H3K27ac, thereby repressing the expression of these genes. Such a transcriptional repressive function is likely attributed to the ability of SATB1 to recruit HDAC1. Treating Satb1 conditional knockout mice with the inhibitor of the CC chemokine receptor alleviated inflammatory cell infiltration and autoimmune phenotypes. Collectively, these results demonstrate that Satb1 plays a critical role in regulating chemokine expression and preventing inflammatory cell infiltration, providing new perspectives on the understanding and clinical treatment of autoimmune diseases.