TRIM33 switches off Ifnb1 gene transcription during the late phase of macrophage activation

Federica Ferri (1, 2, 3) , Aude Parcelier (1, 2) , Vanessa Petit (1, 2) , Anne-Sophie Gallouët (1, 2) , Daniel Lewandowski (1, 2) , Marion Dalloz (1, 2) , Anita van den Heuvel (4) , Petros Kolovos (4) , Eric Soler (1, 2, 4) , Mario Leonardo Squadrito (5) , Michele de Palma (5) , Irwin Davidson (6) , Germain Rousselet (1, 2) , Paul-Henri Romeo (1, 2)

1 LRTS - Laboratoire de Recherche sur la Réparation et la Transcription dans les Cellules Souches
2 SCSR (U_967) - Stabilité génétique, Cellules Souches et Radiations
3 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
4 Erasmus MC - Erasmus University Medical Center [Rotterdam]
5 ISREC - Swiss Institute for Experimental Cancer Research - Lausanne
6 IGBMC - Institut de génétique et biologie moléculaire et cellulaire

Despite its importance during viral or bacterial infections, transcriptional regulation of the interferon-β gene (Ifnb1) in activated macrophages is only partially understood. Here we report that TRIM33 deficiency results in high, sustained expression of Ifnb1 at late stages of toll-like receptor-mediated activation in macrophages but not in fibroblasts. In macrophages, TRIM33 is recruited by PU.1 to a conserved region, the Ifnb1 Control Element (ICE), located 15 kb upstream of the Ifnb1 transcription start site. ICE constitutively interacts with Ifnb1 through a TRIM33-independent chromatin loop. At late phases of lipopolysaccharide activation of macrophages, TRIM33 is bound to ICE, regulates Ifnb1 enhanceosome loading, controls Ifnb1 chromatin structure and represses Ifnb1 gene transcription by preventing recruitment of CBP/p300. These results characterize a previously unknown mechanism of macrophage-specific regulation of Ifnb1 transcription whereby TRIM33 is critical for Ifnb1 gene transcription shutdown.

Domaines: Sciences du Vivant [q-bio]

Federica Ferri, Aude Parcelier, Vanessa Petit, Anne-Sophie Gallouët, Daniel Lewandowski, et al.. TRIM33 switches off Ifnb1 gene transcription during the late phase of macrophage activation. Nature Communications, 2015, 6 (1), ⟨10.1038/ncomms9900⟩. ⟨cea-01820430⟩