biostudies-literatureCilenti FEuropean Research Council1665-1682.e14https://www.ebi.ac.uk/biostudies/studies/S-EPMC8362890biostudies-literatureUnknown54(8)Tight control of inflammatory gene expression by antagonistic environmental cues is key to ensure immune protection while preventing tissue damage. Prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) modulates macrophage activation during homeostasis and disease, but the underlying mechanisms remain incompletely characterized. Here we dissected the genomic properties of lipopolysaccharide (LPS)-induced genes whose expression is antagonized by PGE<sub>2</sub>. The latter molecule targeted a set of inflammatory gene enhancers that, already in unstimulated macrophages, displayed poorly permissive chromatin organization and were marked by the transcription factor myocyte enhancer factor 2A (MEF2A). Deletion of MEF2A phenocopied PGE<sub>2</sub> treatment and abolished type I interferon (IFN I) inductImmunityA PGE<sub>2</sub>-MEF2A axis enables context-dependent control of inflammatory gene expression.PMC8362890725038759532Cuzzola VBarresi SMiotto PCilenti FOstuni RMezzanzanica LCaronni NGenua MLusito ELazarevic DIodice DBarbiera GIannacone MVittoria FMDi Lucia PCirillo DMMontaldo EfalseA PGE<sub>2</sub>-MEF2A axis enables context-dependent control of inflammatory gene expression.Tight control of inflammatory gene expression by antagonistic environmental cues is key to ensure immune protection while preventing tissue damage. Prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) modulates macrophage activation during homeostasis and disease, but the underlying mechanisms remain incompletely characterized. Here we dissected the genomic properties of lipopolysaccharide (LPS)-induced genes whose expression is antagonized by PGE<sub>2</sub>. The latter molecule targeted a set of inflammatory gene enhancers that, already in unstimulated macrophages, displayed poorly permissive chromatin organization and were marked by the transcription factor myocyte enhancer factor 2A (MEF2A). Deletion of MEF2A phenocopied PGE<sub>2</sub> treatment and abolished type I interferon (IFN I) induct2021-01-01T00:00:00Z2021 Aug2026-05-08T15:51:13.915Z2025-02-19T00:04:31.419ZS-EPMC83628903412984010.1016/j.immuni.2021.05.016