A genetic variant controls interferon-β gene expression in human myeloid cells by preventing C/EBP-β binding on a conserved enhancer
Autoři:
Anaïs Assouvie aff001; Maxime Rotival aff002; Juliette Hamroune aff003; Didier Busso aff004; Paul-Henri Romeo aff001; Lluís Quintana-Murci aff002; Germain Rousselet aff001
Působiště autorů:
Laboratoire Réparation et Transcription dans les cellules Souches, UMRE008 Stabilité Génétique Cellules Souches et Radiations, Université de Paris, Université Paris-Saclay, CEA/IRCM, Inserm U1274, Fontenay-aux-Roses, France
aff001; Unit of Human Evolutionary Genetics, CNRS UMR2000, Institut Pasteur, Paris, France
aff002; Plate-forme Génomique, Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
aff003; CIGEx, UMRE008 Stabilité Génétique Cellules Souches et Radiations, Université de Paris, Université Paris-Saclay, CEA/IRCM, Inserm U1274, Fontenay-aux-Roses, France
aff004; Chair Human Genomics & Evolution, Collège de France, Paris, France
aff005
Vyšlo v časopise:
A genetic variant controls interferon-β gene expression in human myeloid cells by preventing C/EBP-β binding on a conserved enhancer. PLoS Genet 16(11): e1009090. doi:10.1371/journal.pgen.1009090
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009090
Souhrn
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 gene IFNB1 is strictly controlled. We have previously shown that in mice, the TRIM33 protein restrains Ifnb1 transcription in activated myeloid cells through an upstream inhibitory sequence called ICE. Here, we show that the deregulation of Ifnb1 expression observed in murine Trim33-/- macrophages correlates with abnormal looping of both ICE and the Ifnb1 gene to a 100 kb downstream region overlapping the Ptplad2/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 the Ifnb1 promoter to activation. In humans, the orthologous region contains several single nucleotide polymorphisms (SNPs) known to be associated with decreased expression of IFNB1 in activated monocytes, and loops to the IFNB1 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 establish a link between a genetic variant preventing binding of a transcription factor and a higher order phenotype, and suggest that the frequent minor allele (around 30% worldwide) might be associated with phenotypes regulated by IFN-β expression in myeloid cells.
Klíčová slova:
Bone marrow cells – Gene expression – Luciferase – Macrophages – Mammalian genomics – Monocytes – Single nucleotide polymorphisms – Transcription factors
Zdroje
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