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The STAT3-SETDB2 Axis Dictates NFκB-mediated Inflammation in Macrophages during Wound Repair

ABSTRACT: Macrophage transition from an inflammatory to reparative phenotype after tissue injury is controlled by epigenetic enzymes that regulate inflammatory gene expression. We have previously identified the histone methyltransferase, SETDB2, in macrophages drives tissue repair by repressing NFκB-mediated inflammation. Complementary ATAC and RNA sequencing of wound macrophages isolated from mice deficient in SETDB2 in myeloid cells revealed that SETDB2 suppresses the inflammatory gene program by inhibiting chromatin accessibility at NFkB-dependent gene promoters. We found that STAT3 was required for SETDB2 expression in macrophages yet, paradoxically, it also functioned as a binding partner of SETDB2 where it repressed SETDB2 activity by inhibiting its interaction with the NFKB component, RELA, leading to increased RELA/NFKB-mediated inflammatory gene expression. Further, RNA sequencing in wound macrophages from STAT3-deficient mice corroborated this and revealed STAT3 and SETDB2 transcriptionally co-regulate overlapping genes. Finally, in diabetic wound macrophages STAT3 expression and STAT3-SETDB2 binding were increased. As such, we identify what we believe to be a novel SETDB2-STAT3 axis that modulates macrophage phenotype during tissue repair and may be an important therapeutic target for nonhealing diabetic wounds.

ORGANISM(S): Mus musculus

PROVIDER: GSE274112 | GEO | 2024/11/06

REPOSITORIES: GEO

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The STAT3-SETDB2 Axis Dictates NFκB-mediated Inflammation in Macrophages during Wound Repair

Project description:The STAT3-SETDB2 Axis Dictates NFκB-mediated Inflammation in Macrophages during Wound Repair

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Project description:Histone H3 lysine 9 tri-methyltransferases (H3K9me3) are related to transcriptional gene silencing. Although SETDB2 has H3K9me3 activity, it is unknown whether SETDB2 is linking to carcinogenesis. Here, we studied alterations and functions of SETDB2 in gastric cancers (GCs). In human clinical samples, overexpression of SETDB2 protein was observed in 30 of 72 (41.7%) primary GC tissues compared with their normal counterparts, and significantly associated with poor prognosis of the patients (P<0.05). SETDB2 protein was significantly detected in late stage of GCs. Moreover, SETDB2 protein was strongly expressed in four (30.8%) of 13 GC cell lines, and knockdown of SETDB2 led to decrease the cell proliferation, migration and invasion. According to the microarray analysis on a GC cell line after knockdown of SETDB2, the expression of WWOX and CADM1 tumor suppressor genes was significantly up-regulated. ChIP analysis showed that the H3K9me3 levels at the promoter regions of WWOX and CADM1 genes were closely regulated by the SETDB2 in GC cells. We also found that SETDB2 bound to the promoter regions after SETDB2 overexpression. Our data suggest that SETDB2 is associated with transcriptional repression of WWOX and CADM1, through H3K9me3, and hence overexpression of SETDB2 may contribute to gastric progression. Transfection of SETDB2 siRNA into MKN74 cells were performed by electroporation. After 48hrs, cells were harvested. Total RNA was used for cDNA microarray.

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