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Interferon stimulated binding of ISRE is cell type specific and is predicted by homeostatic chromatin state.

ABSTRACT: The type I interferon (IFN) signaling pathway involves binding of the transcription factor ISGF3 to IFN-stimulated response elements, ISREs. Gene expression under IFN stimulation is known to vary across cell types, but variation in ISGF3 binding to ISRE across cell types has not been characterized. We examined ISRE binding patterns under IFN stimulation across six cell types using existing ChIPseq datasets. We find that ISRE binding is largely cell specific for ISREs distal to transcription start sites (TSS) and largely conserved across cell types for ISREs proximal to TSS. We show that bound ISRE distal to TSS associate with differential expression of ISGs, although at weaker levels than bound ISRE proximal to TSS. Using existing ATACseq and ChIPseq datasets, we show that the chromatin state of ISRE at homeostasis is cell type specific and is predictive of cell specific, ISRE binding under IFN stimulation. Our results support a model in which the chromatin state of ISRE in enhancer elements is modulated in a cell type specific manner at homeostasis, leading to cell type specific differences in ISRE binding patterns under IFN stimulation.

SUBMITTER: Leviyang S

PROVIDER: S-EPMC8361084 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Butyrate is an abundant metabolite produced by gut microbiota. While butyrate is a known histone deacetylase inhibitor that activates expression of many genes involved in immune system pathways, its effects on virus infections and on the antiviral type I interferon (IFN) response have not been adequately investigated. We found that butyrate increases cellular infection with viruses relevant to human and animal health, including influenza virus, reovirus, HIV-1, human metapneumovirus, and vesicular stomatitis virus. Mechanistically, butyrate suppresses levels of specific antiviral IFN-stimulated gene (ISG) products, such as RIG-I and IFITM3, in human and mouse cells without inhibiting IFN-induced phosphorylation or nuclear translocation of the STAT1 and STAT2 transcription factors. Accordingly, we discovered that although butyrate globally increases baseline expression of more than 800 cellular genes, it strongly represses IFN-induced expression of 60% of ISGs and upregulates 3% of ISGs. Our findings reveal that there are differences in the IFN responsiveness of major subsets of ISGs depending on the presence of butyrate in the cell environment, and overall, they identify a new mechanism by which butyrate influences virus infection of cells.IMPORTANCE Butyrate is a lipid produced by intestinal bacteria. Here, we newly show that butyrate reprograms the innate antiviral immune response mediated by type I interferons (IFNs). Many of the antiviral genes induced by type I IFNs are repressed in the presence of butyrate, resulting in increased virus infection and replication. Our research demonstrates that metabolites produced by the gut microbiome, such as butyrate, can have complex effects on cellular physiology, including dampening of an inflammatory innate immune pathway resulting in a proviral cellular environment. Our work further suggests that butyrate could be broadly used as a tool to increase growth of virus stocks for research and for the generation of vaccines.

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Interferon stimulated binding of ISRE is cell type specific and is predicted by homeostatic chromatin state.

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