SETDB1 Deficiency Promotes Intestinal Inflammation By Regulating YAP And NLRP3

Objective Inflammation bowel disease（IBD）is a global chronic intestinal inflammatory disease which mainly includes ulcerative colitis（UC）and Crohn’s disease（CD）.SETDB1 is a protein lysine methyltransferase that methylates histone H3 at lysine 9（H3K9）and can suppress the expression of downstream genes.Consequently,the major purpose of our research was to explore the specific mechanism of SETDB1 in the pathogenesis of IBD.Methods We collected clinical specimens from IBD patients and healthy volunteers,and detected the expression of SETDB1 by WB and RT-qPCR.Then,we also constructed SETDB1^ΔIECfl/-mice.The pathological manifestations and clinical features of enteritis in mice were judged by weight monitoring assessment,H&E staining and colon length.Meanwhile,TNF-α was used to stimulate HT29 cells to construct an inflammation model in vitro.siRNA was used to silence SETDB1.We detect changes in inflammatory factors via RT-qPCR to observe the severity of inflammation.The expression changes of YAP and NLRP3 were detected by WB and RT-qPCR,and the relationship among SETDB1,YAP and NLRP3 was analyzed by WB and ChIP-PCR.DNA damage was detected by WB and immunofluorescences.Results SETDB1 is downexpressed in inflammatory tissues and cells,and the loss of SETDB1 causes heavier inflammatory response in vitro and vivo.SETDB1deficiency reduces its occupancy on YAP promoter loci to promote transcription and and is more likely to cause DNA damage,which activates the phosphorylation of YAP at Y357,finally promotes the expression of NLRP3,eventually exacerbating the inflammatory response.Conclusions SETDB1 deficiency promotes the expression of YAP and actives phosphorylation of YAP at Y357,which ultimately increases the expression of NLRP3 and promotes the occurrence of inflammatory bowel disease.