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Tytuł:
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The histone methyltransferase SETD2 modulates oxidative stress to attenuate experimental colitis.
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Autorzy:
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Liu M; State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
Rao H; State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
Liu J; State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
Li X; State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
Feng W; State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
Gui L; State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
Tang H; State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.
Xu J; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
Gao WQ; State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China. Electronic address: .
Li L; State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China. Electronic address: .
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Źródło:
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Redox biology [Redox Biol] 2021 Jul; Vol. 43, pp. 102004. Date of Electronic Publication: 2021 May 13.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Original Publication: [Amsterdam]: Elsevier, B.V., [2013]-
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MeSH Terms:
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Colitis*/genetics
Epigenesis, Genetic*
Animals ; Colon/metabolism ; Dextran Sulfate ; Disease Models, Animal ; Histone Methyltransferases/metabolism ; Histone-Lysine N-Methyltransferase/genetics ; Histone-Lysine N-Methyltransferase/metabolism ; Humans ; Mice ; Mice, Inbred C57BL ; Oxidative Stress
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Contributed Indexing:
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Keywords: Epithelial barrier; IBD; Oxidative stress; ROS; SETD2
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Substance Nomenclature:
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9042-14-2 (Dextran Sulfate)
EC 2.1.1.- (Histone Methyltransferases)
EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
EC 2.1.1.43 (SETD2 protein, human)
EC 2.1.1.43 (SETD2 protein, mouse)
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Entry Date(s):
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Date Created: 20210521 Date Completed: 20210705 Latest Revision: 20220531
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Update Code:
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20240104
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PubMed Central ID:
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PMC8141928
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DOI:
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10.1016/j.redox.2021.102004
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PMID:
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34020310
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Epigenetic regulation disorder is important in the onset and pathogenesis of inflammatory bowel disease (IBD). SETD2, a trimethyltransferase of histone H3K36, is frequently mutated in IBD samples with a high risk of developing colorectal cancer (CRC). However, functions of SETD2 in IBD and colitis-associated CRC remain largely undefined. Here, we found that SETD2 modulates oxidative stress to attenuate colonic inflammation and tumorigenesis in mice. SETD2 expression became decreased in IBD patients and dextran sodium sulfate (DSS)-induced colitic mice. Setd2 Vil-KO mice showed increased susceptibility to DSS-induced colitis, accompanied by more severe epithelial barrier disruption and markedly increased intestinal permeability that subsequently facilitated inflammation-associated CRC. Mechanistically, we found that Setd2 depletion resulted in excess reactive oxygen species (ROS) by directly down-regulating antioxidant genes, which led to defects in barrier integrity and subsequently inflammatory damage. Moreover, overexpression of antioxidant PRDX6 in Setd2 Vil-KO intestinal epithelial cells (IECs) largely alleviated the overproductions of ROS and improved the cellular survival. Together, our findings highlight an epigenetic mechanism by which SETD2 modulates oxidative stress to regulate intestinal epithelial homeostasis and attenuate colonic inflammation and tumorigenesis. SETD2 might therefore be a pivotal regulator that maintains the homeostasis of the intestinal mucosal barrier.
(Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)
