tetano
Editor, Senior Moderator
iScience
. 2025 May 11;28(6):112632.
doi: 10.1016/j.isci.2025.112632. eCollection 2025 Jun 20. Targeting G9a-m[SUP]6[/SUP]A translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae
Adil Muneer[SUP] 1 [/SUP], Ling Xie[SUP] 1 [/SUP], Xuping Xie[SUP] 2 3 [/SUP], Feng Zhang[SUP] 4 [/SUP], John A Wrobel[SUP] 1 [/SUP], Yan Xiong[SUP] 5 [/SUP], Xufen Yu[SUP] 5 [/SUP], Charles Wang[SUP] 6 [/SUP], Ciprian Gheorghe[SUP] 6 [/SUP], Ping Wu[SUP] 7 [/SUP], Juan Song[SUP] 8 [/SUP], Guo-Li Ming[SUP] 4 [/SUP], Jian Jin[SUP] 5 [/SUP], Hongjun Song[SUP] 4 [/SUP], Pei-Yong Shi[SUP] 2 7 3 [/SUP], Xian Chen[SUP] 1 9 [/SUP]
Affiliations
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.
Keywords: Biological sciences; Microbiology; Natural sciences; Virology.
. 2025 May 11;28(6):112632.
doi: 10.1016/j.isci.2025.112632. eCollection 2025 Jun 20. Targeting G9a-m[SUP]6[/SUP]A translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae
Adil Muneer[SUP] 1 [/SUP], Ling Xie[SUP] 1 [/SUP], Xuping Xie[SUP] 2 3 [/SUP], Feng Zhang[SUP] 4 [/SUP], John A Wrobel[SUP] 1 [/SUP], Yan Xiong[SUP] 5 [/SUP], Xufen Yu[SUP] 5 [/SUP], Charles Wang[SUP] 6 [/SUP], Ciprian Gheorghe[SUP] 6 [/SUP], Ping Wu[SUP] 7 [/SUP], Juan Song[SUP] 8 [/SUP], Guo-Li Ming[SUP] 4 [/SUP], Jian Jin[SUP] 5 [/SUP], Hongjun Song[SUP] 4 [/SUP], Pei-Yong Shi[SUP] 2 7 3 [/SUP], Xian Chen[SUP] 1 9 [/SUP]
Affiliations
- PMID: 40510117
- PMCID: PMC12159498
- 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.
Keywords: Biological sciences; Microbiology; Natural sciences; Virology.