GPS2 sensitizes IL4 pathway via the recruitments of KDM1A

Here, we systemically investigated the GPS2 corepressor complex function on cyclooxygenase 1 (Ptgs1) in macrophage M2 activation. We found the inflammatory states changed the DNA topology structure along with the histone modification and the gene expression on Ptgs1 locus. GPS2 related NCOR/SMRT corepressor physically bound to Ptgs1 promoter and enhancer, and depletion of all corepressor subunits caused the basal overexpression of Ptgs1 along with the H3K27ac activation. The corepressor subunits display a conserved function on Ptgs1 expression in M2 activation and this regulation is dependent on STAT6 but not through the direct interaction. We find the GPS2 depletion interferences the DNA accessibility on Ptgs1 locus and promotes the enhancer-promoter interaction and the transcriptional process in M2 activation. We further find the GPS2 depletion caused the recruitments of KDM1A, which specifically demethylated the H3K9me2/3 on Ptgs1 locus. In summary, these findings suggest a new paradigm of the corepressor mediated common gene repression in M2 activation and indicate the potential function of the GPS2/NCOR/SMRT function in the tissue homeostasis and wound healing during Th2-mediated immune responses. Overall design: Use the ChIP-seq, 4C-seq, ATAC-seq, and CUT&Tag to uncover the regulation mechanism at the molecular level on IL4 target gene expression in M2 activation and reveal a new function of GPS2 in this process.