{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSETDB2 (also known as CLLD8 or KMT1F) is a histone H3 lysine 9 trimethyltransferase that plays a central role in establishing repressive chromatin architecture. Through the deposition of the H3K9me3 mark, SETDB2 contributes not only to heterochromatin formation at interspersed repetitive and centromeric regions but also to transcriptional gene silencing, ensuring proper chromosome condensation and segregation. These functions support normal chromatin dynamics and secure genomic stability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn immune contexts, SETDB2 has emerged as a key epigenetic regulator of inflammatory gene expression. In macrophages, SETDB2 is upregulated by cytokine and interferon signals and exerts its function by trimethylating H3K9 at NF‐κB binding sites, thereby suppressing transcription of proinflammatory cytokines and mediating the transition from an inflammatory to a reparative state during wound repair. A similar mechanism is observed during viral infections such as influenza and coronavirus, where SETDB2 modulates both antiviral gene programs and the amplitude of the cytokine response. Such regulation helps to temper inflammation and, when disrupted (for example, in diabetic wounds), contributes to a persistent inflammatory phenotype."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in normal tissue repair and host defense, aberrant SETDB2 activity has been implicated in tumorigenesis and developmental processes. In various cancers—including gastric cancer, acute lymphoblastic leukemia, and renal as well as lung carcinomas—overexpression of SETDB2 is correlated with advanced disease stage, poor prognosis, and chemoresistance, primarily through the epigenetic silencing of key tumor suppressor genes. In addition, functional polymorphisms within SETDB2 associate with IgE levels and have been linked to handedness, suggesting that modulation of its methyltransferase activity affects both allergic responses and left–right asymmetry in the central nervous system. Collectively, these observations underscore the dual roles of SETDB2 in maintaining normal epigenetic regulation and contributing to disease when dysregulated."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Claire Falandry, Geneviève Fourel, Vincent Galy, et al. 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