Genome organizer SATB1 restrains the BACH1-cMAF axis that drives autoimmunity

Abstract

The establishment of central tolerance in the thymus is governed by precise gene regulatory networks, but how disrupted chromatin architecture leads to autoimmunity is unclear. The genome organizer SATB1 is essential for T cell development and its loss triggers a severe autoimmune phenotype. Here, we identify a pathogenic transcriptional axis, involving BACH1 and cMAF, that is unleashed upon SATB1 deletion. Using integrated multi-omics in T cell-specific Satb1-knockout mice, we demonstrate that SATB1 constrains BACH1 chromatin occupancy. In its absence, BACH1 redistributes to promoter-proximal regions and SATB1-bound immune loci, where it facilitates the recruitment of the transcription factor cMAF. This BACH1-cMAF complex drives a pro-inflammatory transcriptional program in thymocytes, which seeds the periphery and results in a systemic autoimmune disease. Strikingly, genetic ablation of Bach1 in Satb1-deficient mice rescues the pathology, normalizes immunity and prevents mortality. Furthermore, genetic or pharmacological inhibition of cMAF ameliorates the disease. The pro-inflammatory signature in mutant T cells overlaps with T cells from Systemic Lupus Erythematosus (SLE) patients. Our findings reveal a BACH1-cMAF axis that is derepressed upon SATB1 loss and bridges disrupted thymic chromatin organization to peripheral autoimmunity, nominating new therapeutic targets.