Silencing of double stranded RNA sensing is required for early embryonic development

The type I interferon (IFN) response is inactive during early mammalian development and becomes functional only after gastrulation. As a result, the totipotent and pluripotent embryonic stages remain susceptible to pathogens, including viruses. Here, we demonstrate that pluripotent mouse embryonic stem cells (mESCs) suppress the RIG-I-like receptor sensing pathway by silencing the expression of the dsRNA sensor MDA5. This silencing is necessary to avoid the recognition of dsRNAs of endogenous origin, which accumulate in mESCs. Reintroducing MDA5 results in recognition of these endogenous dsRNAs and triggers the activation of the IFN response through IRF3. The production of IFN alters the differentiation ability of mESCs, and affects the pluripotency gene expression program, as shown by epigenetic, transcriptomic and proteomic analyses. These findings are conserved in zebrafish, where MDA5 is also expressed at later developmental stages. Similarly, zebrafish lack early-stage IFN activation, and dsRNA-mediated signalling results in developmental defects. Altogether, we conclude that silencing the RIG-I-like receptor pathway during early development is widely conserved and is essential to prevent aberrant immune recognition of endogenous dsRNAs, safeguarding normal development. Overall design: ATAC-seq profiling of WT and inducible Mda5 overexpression at 0 hr (- dox) and 24 hr (+dox) in v6.5 mouse ESC cultured in serum+mlif medium.