title: Lysine Methyltransferase SETD7 (SET7/9) Regulates ROS Signaling through mitochondria and NFE2L2/ARE pathway.
abstract: Reactive oxygen species (ROS) homeostasis requires stringent regulation. ROS imbalance, especially ROS accumulation, has profound implications in various disease pathogenesis. Lysine methylation of histone and non-histone proteins has been implicated in various cellular responses. The main objective of this study is to investigate the role of SET domain containing lysine methyltransferase SETD7 (SET7/9) in the regulation of ROS-mediated signaling. Here we report that inhibition of SETD7 with siRNA or a SETD7 small molecule inhibitor in both macrophages and a human bronchial epithelial cell line (Beas-2B) were able to counter NF-ĸB-induced oxidative stress and pro-inflammatory cytokine production. Meanwhile, inhibition of SETD7 elevates mitochondria antioxidant functions via negative regulation of PPARGC1A and NFE2L2. Using a co-expression system and purified proteins, we detected direct interaction between SETD7 and NFE2L2. These results indicate that lysine methylation by SETD7 is important for the fine-tuning of ROS signaling through its regulation on pro-inflammatory responses, mitochondrial function and the NFE2L2/ARE pathway. Up-regulation of multiple antioxidant genes and improved ROS clearance by inhibition of SETD7 suggests the potential benefit of targeting SETD7 in treating ROS-associated diseases.
authors.affiliation: Inflammation and Immunology Research Unit, Pfizer Research, Cambridge, MA 02139.
authors.forename: Shuying
authors.initials: S
authors.lastname: He
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139.
authors.forename: Dafydd R
authors.initials: DR
authors.lastname: Owen
authors.affiliation: Inflammation and Immunology Research Unit, Pfizer Research, Cambridge, MA 02139.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Jelinsky
authors.affiliation: Inflammation and Immunology Research Unit, Pfizer Research, Cambridge, MA 02139.
authors.forename: Lih-Ling
authors.initials: LL
authors.lastname: Lin
mesh_terms: D061745:Antioxidant Response Elements; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D011495:Histone-Lysine N-Methyltransferase / Q000502:physiology*; D006801:Humans; D008928:Mitochondria / Q000201:enzymology*; D063154:Mitochondrial Dynamics; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation; D000099156:Superoxide Dismutase 2
chemical_list: D002374:Catalase; D016207:Cytokines; D011495:Histone-Lysine N-Methyltransferase; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D014157:Transcription Factors; D000099156:Superoxide Dismutase 2; C495635:NFE2L2 protein, human; C486497:PPARGC1A protein, human; C540312:SETD7 protein, human