Epigenetic modifications control the phenotype of alternatively activated macrophages (136.4)

Abstract Although alternatively activated (M2) macrophages play critical roles in chronic diseases, little is known about the acquisition and maintenance of their phenotype. We investigated the mechanisms whereby chromatin remodeling can influence the expression of genes that define M2 macrophages. Bone marrow-derived macrophages were incubated with IL-4 (10 ng/ml) and the expression of M2 marker genes (Ym1 and found in inflammatory zone-1 (FIZZ1)) and the histone H3 lysine-27 demethylase Jmjd3 was measured by PCR. ChIP assays were performed to determine levels of histone H3 lysine-4 trimethylation (H3K4me3), histone H3 lysine-27 trimethylation (H3K27me3), and Jmjd3 associated with the promoter regions of Ym1 and FIZZ1. Macrophages treated with IL-4 were found to increase the expression of mRNA levels of Ym1 and FIZZ1. Concomitant with this augmented expression pattern were an increase in H3K4me3 levels and a decrease in H3K27me3 levels; a pattern consistent with enhanced gene expression. Furthermore, Jmjd3 mRNA and Jmjd3 recruitment to Ym1 and FIZZ1 genes were increased in macrophages treated with IL-4, suggesting that Jmjd3 participates in erasing H3K27me3 marks on the promoter regions of Ym1 and FIZZ1. We conclude that the M2-macrophage phenotype is epigenetically regulated, in part, via induction of the H3K27 demethylase Jmjd3. (NIH grants P01-HL031963, HL092845, HL89216 and HL031237)