Regulatory T cells (T(reg) cells) are essential for self-tolerance and immune 
homeostasis. Lack of effector T cell (T(eff) cell) function and gain of 
suppressive activity by T(reg) cells are dependent on the transcriptional 
program induced by Foxp3. Here we report that repression of SATB1, a genome 
organizer that regulates chromatin structure and gene expression, was crucial 
for the phenotype and function of T(reg) cells. Foxp3, acting as a 
transcriptional repressor, directly suppressed the SATB1 locus and indirectly 
suppressed it through the induction of microRNAs that bound the SATB1 3' 
untranslated region. Release of SATB1 from the control of Foxp3 in T(reg) cells 
caused loss of suppressive function, establishment of transcriptional T(eff) 
cell programs and induction of T(eff) cell cytokines. Our data support the 
proposal that inhibition of SATB1-mediated modulation of global chromatin 
remodeling is pivotal for maintaining T(reg) cell functionality.