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Non-canonical function of histone methyltransferase G9a in the translational regulation of chronic inflammation.
Muneer, Adil; Wang, Li; Xie, Ling; Zhang, Feng; Wu, Bing; Mei, Liu; Lenarcic, Erik M; Feng, Emerald Hillary; Song, Juan; Xiong, Yan; Yu, Xufen; Wang, Charles; Jain, Kanishk; Strahl, Brian D; Cook, Jeanette Gowen; Wan, Yisong Y; Moorman, Nathaniel John; Song, Hongjun; Jin, Jian; Chen, Xian.
Affiliation
  • Muneer A; Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Wang L; Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Xie L; Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Zhang F; Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Wu B; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Mei L; Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Lenarcic EM; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Feng EH; Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Song J; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Xiong Y; Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Yu X; Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Wang C; Center for Genomics, Division of Microbiology & Molecular Genetics, Department of Basic Sciences, Loma Linda University, Loma Linda, CA 92350, USA.
  • Jain K; Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Strahl BD; Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Cook JG; Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hi
  • Wan YY; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Moorman NJ; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Song H; Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Jin J; Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Chen X; Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: xianc@email.unc.edu.
Cell Chem Biol ; 30(12): 1525-1541.e7, 2023 12 21.
Article in En | MEDLINE | ID: mdl-37858336
ABSTRACT
We report a novel translation-regulatory function of G9a, a histone methyltransferase and well-understood transcriptional repressor, in promoting hyperinflammation and lymphopenia; two hallmarks of endotoxin tolerance (ET)-associated chronic inflammatory complications. Using multiple approaches, we demonstrate that G9a interacts with multiple translation regulators during ET, particularly the N6-methyladenosine (m6A) RNA methyltransferase METTL3, to co-upregulate expression of certain m6A-modified mRNAs that encode immune-checkpoint and anti-inflammatory proteins. Mechanistically, G9a promotes m6A methyltransferase activity of METTL3 at translational/post-translational level by regulating its expression, its methylation, and its cytosolic localization during ET. Additionally, from a broader view extended from the G9a-METTL3-m6A translation regulatory axis, our translatome proteomics approach identified numerous "G9a-translated" proteins that unite the networks associated with inflammation dysregulation, T cell dysfunction, and systemic cytokine response. In sum, we identified a previously unrecognized function of G9a in protein-specific translation that can be leveraged to treat ET-related chronic inflammatory diseases.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Histone-Lysine N-Methyltransferase / Histocompatibility Antigens / Inflammation Limits: Humans Language: En Journal: Cell Chem Biol Year: 2023 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Histone-Lysine N-Methyltransferase / Histocompatibility Antigens / Inflammation Limits: Humans Language: En Journal: Cell Chem Biol Year: 2023 Type: Article Affiliation country: United States