How DUXC-family transcription factors influence immune signaling: implications for muscular dystrophy, cancer, and early development

Abstract

DUXC-family transcription factors are endogenously expressed at the cleavage stage of development in placental mammals and help drive an initial burst of zygotic gene transcription. However, misexpression of the human ortholog DUX4 in adult skeletal muscle is the causative factor in Facioscapulohumeral muscular dystrophy (FSHD). Additionally, expression of DUX4 in solid cancers leads to downregulation of MHC-I antigen presentation machinery and is correlated with immune evasion. Here, I show that DUX4 also suppresses the transcriptional response to Type-II interferon gamma (IFNg), Type-I interferon beta (IFNb), double stranded (ds)RNA, and dsDNA treatments. A transcriptionally silent C-terminal portion of the DUX4 protein interacts with activated forms of STAT1, reduces its binding at interferon stimulated gene (ISG) promoters, and destabilizes assembly of the transcriptional complex, thus preventing ISG upregulation. Transcriptional suppression of ISGs requires conserved (L)LxxL(L) motifs in the carboxyterminal region of DUX4 and phosphorylation of STAT1 Y701 enhances interaction with DUX4. Consistent with these findings, expression of endogenous DUX4 in FSHD muscle cells and the CIC-DUX4 fusion containing the DUX4 CTD in a sarcoma cell line inhibit IFNg-induction of interferon-stimulated genes (ISGs). Mouse Dux similarly interacted with STAT1 and suppressed IFNg induction of ISGs. These findings identify an evolved role of the DUXC family in modulating immune signaling pathways with implications for development, cancers, and FSHD.