Herpesviral induction of germline transcription factor DUX4 is critical for viral gene expression

Abstract

DUX4 is a transcription factor and a master regulator of embryonic genome activation (EGA). During early embryogenesis, EGA is crucial for maternal to zygotic transition at the 8-cell stage in order to overcome silencing of genes and enable transcription from the zygotic genome. In adult somatic cells, DUX4 expression is largely silenced. Activation is likely pathogenic, and in adult muscle cells causes genetic disorder Facioscapulohumeral Muscular Dystrophy (FSHD). We identified activation of DUX4 expression upon lytic replication of the herpesviruses HSV-1, HCMV, EBV and KSHV, but not of adenoviruses, negative strand RNA viruses or positive strand RNA viruses. We demonstrate by RNA-Seq analysis that DUX4 expression upon herpesviral replication leads to the induction of hundreds of DUX4 target genes including germline-specific retroelements as well as several members of the TRIM, PRAMEF and ZSCAN protein families. Moreover, we show that DUX4 expression is a direct consequence of herpesviral infection. DUX4 can be stimulated by overexpression of HSV-1 immediate early proteins, indicating active induction of EGA genes by herpesviral infection. We further show that DUX4 expression is critical for driving HSV-1 gene expression. Our results show that viruses from alpha-, beta- and gamma-herpesvirus subfamilies induce DUX4 expression and downstream germline-specific genes and retroelements. We hypothesize that herpesviruses induce DUX4 expression in order to induce an early embryonic-like transcriptional program that prevents epigenetic silencing of the viral genome and facilitates herpesviral gene expression.

Pioneer factors in viral infection

“…In addition there are reports of DUX4 expression in human cancer. Interestingly, we and other could show, that DUX4 is induced by herpesviral infection (52)(53)(54). DUX4 is expressed upon lytic replication of herpesviruses by viral proteins, and knockout of DUX4 blocks replication of HSV-1 and HSV-2 almost completely.…”

DUX4 double whammy: The transcription factor that causes a rare muscular dystrophy also kills the precursors of the human nose

“…We also suggest that herpesvirus is a relevant environmental modifier as we find that HSV-1 augments DUX4 production in SMCHD1 KO hESC and arhinia and FSHD2 iPSC more so than in WT hESC and control iPSC, respectively. HSV-1 may also induce DUX4 via a DNA damage response and p53 activity (48), although recent studies suggest a direct role for the viral immediate early proteins ICP0 and ICP4 in DUX4 up-regulation (49). HSV-1 is a common sexually transmitted disease among women of reproductive age, and it can, in rare circumstances, be transmitted to the fetus during pregnancy with severe consequences (e.g., microcephaly and fetal demise) (50).…”

DNA virus infections shape transposable elements activity in vitro and in vivo

“…We recently showed that the germline transcription factor DUX4 is expressed in the context of DNA virus infection, namely herpesviruses (HSV-1, HSV-2, HCMV, KSHV and EBV), papillomaviruses (HPV16) and polyomaviruses (MCPyV) (51). Along this line, we wanted to investigate whether herpesviral infections also induce TEs expression in vivo.…”

“…The raw sequencing datasets have been uploaded to the Gene Expression Omnibus (GEO) database, including RNA-Seq of DUX4 over-expression (GSE253543) and RNA-Seq of HCMV infection and KAP1 knockdown (GSE256111). The study used publicly available datasets from GEO, including bulk RNA-seq of HSV-1 infection (GSE59717) (61), ATAC-seq of HSV-1 infection (GSE100611) (62), CHIP-seq of H3K9me3 and H3K27me3 upon HSV-1 infection (GSE124803) (47), CHIP-seq of KAP1 (GSE72622) (63), RNA-seq of DUX4-KO (GSE234489) (51), CHIP-seq of DUX4 (GSM837613 and GSE174759) (64)(51), as well as the single-cell RNA-seq data of nasopharyngeal carcinoma (GSE162025) (65), Head and neck squamous cell carcinoma (GSE164690) (66) and Merkel cell carcinoma tumor (GSE226438) (67). UCSC genome browser session links for the ATAC-seq.…”