Investigation Of The Role And Molecular Mechanisms Of Histone Methyltransferase SETD8 In Anti-HSV-1 Response

Herpes simplex virus(HSV-1)is a double-stranded DNA virus,which is a common clinical pathogen and a major threat to human health.The research on its infection mechanism and the development of therapeutic drugs are very meaningful.More and more reports have revealed the regulatory role of epigenetic factors in the process of HSV-1 infection.These indicate that epigenetic regulation is important in the study of HSV-1 infection.In order to find new epigenetic factors involved in regulating innate immune response to HSV-1,we performed systematic screening with the small molecular inhibitor library,from which we identified UNC0379 as a promising chemical significantly inhibiting the transcription of HSV-1 genes.UNC0379 is an inhibitor of histone H4K20 monomethylase SETD8.The global level of H4K20me1 decreased significantly in the late stage of HSV-1 infection,and that the infection of HSV-1 stabilized the overexpressed SETD8.The result of inhibitor treatment,si RNA knockdown and over-expression experiments,all indicated that inhibition of SETD8 significantly inhibits HSV-1 infection at three levels: HSV-1 gene transcription,DNA copy number and the number of active virus particles after infection.Moreover,SETD8 inhibiton greatly improved the survival rate of host cells under HSV-1 lytic infection.Through the RNA-Seq and H4K20me1 ChIP-Seq,we further found that the treatment of UNC0379 in THP1 cells promoted the transcription of antiviral genes.At the same time,in cells where the cGAS/MITA signaling pathway is defect,UNC0379 also inhibited HSV-1.The results of bioinformatics analysis suggest that besides the antiviral pathways,the genes involved in nucleosome assembly and transcriptional regulation are also enriched.In conclusion,we identified an epigenetics gene involved in the regulation of cell anti-DNA viral response in this study,which provides a new direction for revealing the molecular mechanism of anti-DNA-viruses and provide a potential new target for drug development.