Targeting G9a-m6A translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae
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
iScience, doi:10.1016/j.isci.2025.112632
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.
AUTHOR CONTRIBUTIONS X.C. conceived, designed, supervised the project, and wrote the manuscript. A.M. analyzed and interpreted data and wrote the manuscript. L.X. performed inhibitor treatment, sample preparation and processing for MS/MS experimental analysis and analyzed data. F.Z., H.S., and J.S. performed RNA-seq, MeRIP-seq, and analyzed the data. X.X., P.-Y.S., and P.W. performed inhibitor treatment and collected antiviral and cytotoxicity data. J.A.W. analyzed RNAseq and MeRIP-seq data. Y.X., X.Y., and J.J. provided UNC0965, UNC0642, UNC1999, and MS1262 targeting G9a/Ezh2.
DECLARATION OF INTERESTS X.C. is the founder of TransChromix, LLC. J.J. is a cofounder and equity shareholder in Cullgen, Inc., a scientific cofounder and scientific advisory board member of Onsero Therapeutics, Inc., and a consultant for Cullgen, Inc., EpiCypher, Inc., Accent Therapeutics, Inc, and Tavotek Biotherapeutics, Inc. The Jin laboratory received research funds from Celgene Corporation, Levo Therapeutics Inc., Cullgen, Inc. and Cullinan Oncology, Inc. The indication of using clinically trialed G9a/Ezh2 inhibitors for COVID-19 therapy is protected by US provisional patent application #63/113,211 as ''Use of Method''.
STAR★METHODS Detailed methods are provided in the online version of this paper and include the following:
EXPERIMENTAL MODEL AND STUDY PARTICIPANT DETAILS Cell lines and primary cultures of human origin Human alveolar epithelial cells that overexpress hACE2 receptor..
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