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Title: Inhibition of EHMT2 induces a robust antiviral response against Foot-and-Mouth Disease and Vesicular Stomatitis Virus infections in bovine cells

Author
item SINGH, NEETU - Texas A&M University
item RAMIREZ-CARVAJAL, LISBETH - Texas A&M University
item De Los Santos, Teresa
item GOLDING, MICHAEL - Texas A&M University
item LONG, CHARLES - Texas A&M University

Submitted to: Journal of Interferon and Cytokine Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/18/2015
Publication Date: 9/29/2015
Citation: Singh, N., Ramirez-Carvajal, L., De Los Santos, T.B., Golding, M.C., Long, C.R. 2015. Inhibition of EHMT2 induces a robust antiviral response against Foot-and-Mouth Disease and Vesicular Stomatitis Virus infections in bovine cells. Journal of Interferon and Cytokine Research. 36(1):37-47. doi: 10.1089/jir.2015.0006.

Interpretive Summary: Type I interferons (IFN) are molecules that counteract viral infection. Euchromatic histone-lysine N-methyltransferase 2 (EHMT2; also known as G9a) is an enzyme that contributes to the regulation of gene expression in cells, including IFNs. In the present study, we investigated the role of EHMT2 in the regulation of bovine antiviral immunity and explored its therapeutic potential against foot-and-mouth disease virus (FMDV) and vesicular stomatitis virus (VSV) replication. We demonstrated that treatment of primary bovine cells with an EHMT2 inhibitor before or shortly after virus infection resulted in an increase in IFN, several antiviral genes, and a reduction of viral infection in bovine cells. Better understanding of the regulatory mechanism of EHMT2 over the antiviral response should help to develop new strategies to control viral replication and protect the cattle from infection.

Technical Abstract: The genetic regulatory network controlling the innate immune system is well understood in many species. However, the role of the epigenetic mechanisms underlying the expression of immunoregulatory genes is less clear, especially in livestock species. Histone H3 lysine 9 dimethylation (H3K9me2) is an epigenetic modification associated with transcriptional silencing within the euchromatin regions. Euchromatic histone-lysine N-methyltransferase 2 (EHMT2; also known as G9a) is a crucial enzyme responsible for regulating the dynamics of this epigenetic modification. It has been shown that histone modifications play a role in regulating type I interferon (IFN) response. In the present study, we investigated the role of EHMT2 in the epigenetic regulation of bovine antiviral innate immunity and explored its therapeutic potential against viral infections. We evaluated the effects of pharmacological and RNAi mediated inhibition of EHMT2 on transcription of IFN-Beta and other IFN- inducible antiviral genes as well as its effect on Foot-and-Mouth Disease Virus (FMDV) and Vesicular Stomatitis Virus (VSV) replication in bovine cells. We show that treatment of primary bovine cells with the synthetic EHMT2 inhibitor (UNC0638) either before or shortly after virus infection resulted in a significant increase in transcript levels of bovine IFN-Beta (300 fold ) and other IFN-inducible genes including ISG-15, Mx-1, Mx-2, RIG-I, OAS-1 and PKR. Expression of these factors correlated with a significant decrease in VSV and FMDV viral titers. Our data confirm the involvement of EHMT2 in the epigenetic regulation of boIFN Beta and demonstrate the activation of a general antiviral state after EHMT2 inhibition.