SETD3 actin histidine methyltransferase regulates intestinal epithelial barrier integrity and mucosal inflammation

These include increased permeability of the IEC barrier, diminished assembly of the perijunctional F-actin belt, increased cell size, and delayed TJ reassembly during calcium switch. Consistently, SETD3 null mice displayed increased intestinal permeability and decreased labeling intensity of apical β-actin as compared to wildtype controls. Furthermore, SETD3 null mice showed increased cell stemness and proliferation in colonic epithelium without defects in AJ/TJ assembly and secretory cell differentiation.

In addition, SETD3 KO mice developed more severe disease symptoms during dextran sodium sulfate (DSS)-induced colitis, which were accompanied by increased macrophage, T cell and neutrophil infiltration into colonic mucosa and accelerated IEC death. Overall, our data suggests that SETD3 acts as a novel positive regulator of the intestinal epithelial barrier and plays a protective role during intestinal mucosal damage and inflammation.