DNMT1 cooperates with MBD4 to inhibit the expression of Glucocorticoid‐induced TNFR‐related protein in human T cells
Wang S., Li Y., Zhu F., Lin F., Luo X., Zhao B., Zhang P., Li D., Gao Y., Liang R., Liu L., Tsun A., Yuan X., Wu K., Li B.
Glucocorticoid‐induced TNFR‐related protein (GITR) is constitutively expressed in T regulatory (Treg) cells and regulates their suppressive function. We identified two methylated CpG islands in the Gitr locus. Using a ChIP assay, we demonstrate that both DNMT1 and methyl‐CpG‐binding domain Protein 4 (MBD4) bind to the Gitr promoter. Moreover, knockdown of DNMT1 decreases the binding activity of MBD4. We observed much higher levels of both DNMT1 and MBD4 in human CD4+CD25− conventional T (Tconv) cells. Moreover, co‐overexpression of DNMT1 and MBD4 in Treg cells significantly inhibits GITR expression and impairs their suppressive activity. Our results reveal a novel molecular mechanism by which MBD4 inhibits GITR expression in a DNMT1‐dependent manner.