Chromatin remodeler ARID1A binds IRF3 to selectively induce antiviral interferon production in macrophages

Transcription factor IRF3 is critical for the induction of antiviral type I interferon (IFN-I). The epigenetic regulation of IFN-I production in antiviral innate immunity need to be further identified. Here, we report that epigenetic remodeler ARID1A, a critical component of the mSWI/SNF complex, could bind IRF3 and then was recruited to the Ifn-I promoter by IRF3, thus selectively promoting IFN-I but not TNF-a, IL-6 production in macrophages upon viral infection. Myeloid cell-specific deficiency of Arid1a rendered mice more susceptible to viral infection, accompanied with less IFN-I production. Mechanistically, ARID1A facilitates chromatin accessibility of IRF3 at the Ifn-I promoter by interacting with histone methyltransferase NSD2, which methylates H3K4 and H3K36 of promoter region. Our findings demonstrate the new roles of ARID1A and NSD2 in innate immunity, providing insight to the crosstalks of chromatin remodeling, histone modification and transcription factor in the epigenetic regulation of antiviral innate immunity. Overall design: the BMDMs from Arid1a (f/f) cre+ and Arid1a (f/f) cre- (control ) mice infected with VSV for 0h and 8h .