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

by Ana ïs Assouvie, Maxime Rotival, Juliette Hamroune, Didier Busso, Paul-Henri Romeo, Lluis Quintana-Murci, Germain Rousselet

Interferon β (IFN-β) is a cytokine that induces a global antiviral proteome, and regulates the adaptive immune response to infections and tumors. Its effects strongly depend on its level and timing of expression. Therefore, the transcription of its coding geneIFNB1 is strictly controlled. We have previously shown that in mice, the TRIM33 protein restrainsIfnb1 transcription in activated myeloid cells through an upstream inhibitory sequence called ICE. Here, we show that the deregulation ofIfnb1 expression observed in murineTrim33-/- macrophages correlates with abnormal looping of both ICE and theIfnb1 gene to a 100 kb downstream region overlapping thePtplad2/Hacd4 gene. This region is a predicted myeloid super-enhancer in which we could characterize 3 myeloid-specific active enhancers, one of which (E5) increases the response of theIfnb1 promoter to activation. In humans, the orthologous region contains several single nucleotide polymorphisms (SNPs) known to be associated with decreased expression ofIFNB1 in activated monocytes, and loops to theIFNB1 gene. The strongest association is found for the rs12553564 SNP, located in the E5 orthologous region. The minor allele of rs12553564 disrupts a conserved C/EBP- β binding motif, prevents binding of C/EBP-β, and abolishes the activation-induced enhancer activity of E5. Altogether, these results esta...

Source: PLoS Genetics - November 4, 2020 Category: Genetics & Stem Cells Authors: Ana ïs Assouvie Source Type: research