| The change of epigenetics lead to abnormal expression of gene.Setdb1 plays an important role in histone methylation and gene silencing.The abnormal histone methylation induced by setbdl at H3K9 site can silence the expression of tumor suppressor genes,contributing to the occurrence of cancer.What's more,Setbdl is also essential for the normal development of organs and tissues.In addition to the known roles of Setdbl in embryonic development and nervous system development,our research found that Setdbl also plays a crucial part in the small intestine and heart.We identified that Setdb1 deficiency participates in the pathogenesis of IBD and its expression level decreased in IBD patients by analyzing a public database and biopsy specimens collected.The epithelium-specific knockout mice with Setdb1 showed significant intestinal damage and weight loss,and hardly to maintain a long-life cycle.What's more,the deletion of Setdb1 triggered genomic instability and cell death.We confirmed that these cell deaths were not caused by RIP1-independent necrosis,but by necroptosis induced by ZBP1.And the loss of Setdb1 released endogenous retrovirus.The accumulation of ERVs could be sensed by the Z-DNA banding domain of ZBP1 and active the RIP3-MLKL induced necroptosis pathway.Furthermore,genome instability,reactive ERVs,upregulation of ZBP1 and necroptosis were seen in IBD patients.Thus,we suggested that targeting ISCs necroptosis may be a novel strategy for IBD.In addition,we also found that the loss of Setdb1 could lead to the formation of dilated cardiomyopathy in mice.Moreover,we found the loss of Setdb1 caused abnormal metabolism of cardiomyocytes in adult mice,accompanied by decreased ejection fraction and mitochondria damage.And these changes may lead to ferroptosis rather than necroptosis.The study of Setdbl in different tissues not only revealed the complexity of epigenetic regulation mechanism,but also provided a new strategy for the prevention and treatment of diseases. |
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