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Repression of a transcription factor motif cluster within a Tandem Repeat is Required for Immune Homeostasis

ABSTRACT: The innate immune antiviral protein MORC3 restricts transcription of DNA viruses and is frequently inhibited by viruses. To counteract viral antagonism, MORC3 represses type I interferon (IFN), causing viral inhibition of MORC3 to trigger (>10,000-fold) IFN induction. How MORC3 specifically represses IFN and why IFN induction upon MORC3 loss is so potent without canonical IRF/STAT factors is unknown. Here, we show that MORC3 represses a novel class of bifunctional enhancer DNA elements composed of tandem repeats densely populated with up to 80 transcription factor (TF) motifs. At steady state, the high motif density allows TFs to recruit SUMO and MORC3 inducing repression. Disruption of SUMOylation or MORC3 converts these elements into potent enhancers. Specifically, the human IFN-inducing tandem repeat contains approximately 35 PU.1 binding sites, and PU.1 drives IRF/STAT-independent IFN induction upon MORC3 loss. Our findings uncover a TF motif cluster-driven repression mechanism by MORC3 and SUMO at tandem repeats, which is utilized by the innate immune system to specifically repress IFN and potently activate immune defenses upon viral antagonism of MORC3.

ORGANISM(S): Homo sapiens

PROVIDER: GSE301805 | GEO | 2026/03/09

REPOSITORIES: GEO

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Project description:We investigated the roles of IRF-3 and IRF-7 in innate antiviral immunity against dengue virus (DENV). Double-deficient Irf-3-/-7-/- mice infected with the DENV2 strain S221 possessed 1,000-150,000 fold higher levels of viral RNA than wild-type and single-deficient mice 24 hours after infection; however, they remained resistant to lethal infection. IFN-α/β was induced similarly in wild-type and Irf-3-/- mice post DENV infection, whereas in the Irf-7-/- and Irf-3-/-7-/- mice, significantly low levels of IFN-α/β expression was observed within 24 hours post-infection. IFN-stimulated gene (ISG) induction was also delayed in Irf-3-/-7-/- mice relative to wild-type and single-deficient mice. In particular, Cxcl10 and Ifnα2 were rapidly induced independently of both IRF-3 and IRF-7 in the Irf-3-/-7-/- mice with DENV infection. Higher levels of serum IFN-γ, IL-6, CXCL10, IL-8, IL-12 p70, and TNF were also observed in Irf-3-/-7-/- mice 24 hours after infection, at which time point viral titers peaked and started to be cleared. Antibody-mediated blockade experiments revealed that IFN-γ, CXCL10, and CXCR3 function to restrict DENV replication in Irf-3-/-7-/- mice. Additionally, the ISGs Cxcl10, Ifit1, Ifit3, and Mx2 can be induced via an IRF-3- and IRF-7-independent pathway that does not involve IFN-γ signaling for protection against DENV. Collectively, these results demonstrate that IRF-3 and IRF-7 are redundant, albeit IRF-7 plays a more important role than IRF-3 in inducing the initial IFN-α/β response; only the combined actions of IRF-3 and IRF-7 are necessary for efficient control of early DENV infection; and the late, IRF-3- and IRF-7-independent pathway contributes to anti-DENV immunity. To identify the antiviral genes that are controlled by IRF-3 and IRF-7 signaling during DENV infection, we examined a panel of ISG expression in the spleens of wild-type, Irf-3-/-, Irf-7-/- and Irf-3-/-7-/- mice at 12 or 24 hours after DENV infection using a quantitative PCR array kit. The fold changes in expression of 55 genes from infected mice were normalized to that of strain-matched naïve mice.

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Repression of a transcription factor motif cluster within a Tandem Repeat is Required for Immune Homeostasis

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