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A genetic variant controls interferon-β gene expression in human myeloid cells by preventing C/EBP-β binding on a conserved enhancer

ABSTRACT: Interferon beta is a central cytokine in the antiviral response and the immunogenicity of cancer therapies. In monocytes, its expression is modulated by a 60 kb downstream eQTL. We found that this eQTL disrupts binding of the C/EBP-β transcription factor to an enhancer interacting with the IFNB1 promoter. This enhancer, that we have called FIRE for Far IFNB1 Regulatory Enhancer, is conserved in murine myeloid cells, where its looping to Ifnb1 is increased in a genetic model of Ifnb1 deregulation. Precisely, we show that in murine myeloid cells, the TRIM33 chromatin reader partially co-localizes with CTCF and cohesin on the chromatin, and knocking out Trim33 reinforces a loop between Ifnb1 and FIRE.

ORGANISM(S): Mus musculus

PROVIDER: GSE137514 | GEO | 2020/10/09

REPOSITORIES: GEO

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Project description:Macrophage activation during the innate immune response is tightly regulated to prevent tissue damage while activating the defense to cellular attack. Using a mouse model where Trim33 is specifically deleted in mature myeloid cells, we show that TRIM33 is essential for two aspects of the inflammatory response in vivo. Loss of TRIM33 attenuates the initiation of macrophage activation by lipopolysaccharide (LPS) and TRIM33 is necessary to switch off transcription of inflammatory genes during late stages of LPS activation. Using chromatin immunoprecipitation coupled to deep sequencing, we provide a link between TRIM33 binding, RNA Polymerase II occupancy and H3K4me3 spreading on inflammatory genes in macrophages and reveal novel insights concerning the transcriptional regulation of Ifn-beta where TRIM33 exerts a repressive function via a distal regulatory region during late stages of LPS activation of macrophages. These findings pinpoint TRIM33 as a major regulator of the resolution of inflammation and indicate that transcriptional regulators can fine-tune H3K4me3 spreading. To study the role of TRIM33 in the transcriptional response induced by pathogen receptors, we analyzed whether lack of TRIM33 in macrophages affected the TLR-mediated regulation of proinflammatory and antimicrobial genes. To study this role, we bred TRIM33fl/fl mice with Lyz-Cre mice (obtained from The Jackson Laboratory, Bar Harbor, Maine, USA) where the Cre recombinase gene is under the regulatory sequences of the Lyz gene that is expressed only in mature myeloid cells. Bone marrow cells from 2 LyzCre/Trim33+/+ mice and 2 LyzCre/Trim33flox/flox mice were then differentiated in macrophages and treated during 0h, 4h, 12h and 24h with LPS. Total RNA was extracted from macrophages and analysed using cDNA microarrays. The set of gene expression consists of 16 samples of RNA of bone marrow derived macrophages activated with 100ng/ml of LPS during 0h, 4h, 12h, 24h, 8 samples from 2 LyzCre/Trim33+/+ mice and 8 samples from 2 LyzCre/Trim33flox/flox mice.

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A genetic variant controls interferon-β gene expression in human myeloid cells by preventing C/EBP-β binding on a conserved enhancer

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