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Publications

Journal Article Epublish

PubMed: 40510117 DOI: 10.1016/j.isci.2025.112632

Targeting G9a-m 6A translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae.

iScience 28(6):112632

Authors: Adil Muneer, Ling Xie, Xuping Xie, Feng Zhang, John A Wrobel, Yan Xiong, Xufen Yu, Charles Wang, Ciprian Gheorghe, Ping Wu, Juan Song, Guo-Li Ming, Jian Jin, Hongjun Song, Pei-Yong Shi, Xian Chen

Affiliations

  • Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
  • Institute for Human Infections and Immunity, Sealy Institute for Vaccine Sciences, Sealy Center for Structural Biology & Molecular Biophysics, University of Texas Medical Branch, Galveston, TX, USA.
  • Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences, and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Center for Genomics, Division of Microbiology & Molecular Genetics, Department of Basic Sciences, Lawrence D Longo MD Center for Perinatal Biology, Department of Gynecology and Obstetrics, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA.
  • Department of Neuroscience, Cell Biology, and Anatomy, Center for Addiction Sciences and Therapeutics, Brain Health Institute, Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA.
  • Department of Pharmacology, and Neuroscience Center, 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.

Abstract

N6-methyladenosine (m6A) modification pathway is hijacked by several RNA viruses, including SARS-CoV-2, making it an attractive host-directed target for development of broad-spectrum antivirals. Here, we show that histone methyltransferase G9a, through its interaction with METTL3, regulates SARS-CoV-2-mediated rewiring of host m6A methylome to ultimately promote turnover, abundance, secretion and/or phosphorylation of various viral receptors and proteases, transcription factors, cytokines/chemokines, coagulation and angiogenesis associated proteins, and fibrosis markers. More importantly, drugs targeting G9a and its associated protein EZH2 are potent inhibitors of SARS-CoV-2 replication and reverse multi-omic effects of coronavirus infection in human alveolar epithelial cells (A549-hACE2) and COVID-19 patient peripheral blood mononuclear cells (PBMCs)-with similar changes seen in multiorgan autopsy samples from COVID-19 patients. Altogether, we extend G9a function(s) beyond transcription to translational regulation during COVID-19 pathogenesis and show that targeting this master regulatory complex represents a new strategy (drug-class) that can be leveraged to combat emerging anti-viral resistance and infections.

MeSH

Cells, Sars-Cov-2, Pharmaceutical Preparations, Multiple Chronic Conditions, Covid-19, Therapeutics, Severe Acute Respiratory Syndrome-Related Coronavirus, Infections