De Santa Francesca, Totaro Maria Grazia, Prosperini Elena, Notarbartolo Samuele, Testa Giuseppe, Natoli Gioacchino
Department of Experimental Oncology, European Institute of Oncology, Campus IFOM-IEO, Via Adamello 16, 20139 Milan, Italy.
Cell. 2007 Sep 21;130(6):1083-94. doi: 10.1016/j.cell.2007.08.019. Epub 2007 Sep 6.
Epigenetic chromatin marks restrict the ability of differentiated cells to change gene expression programs in response to environmental cues and to transdifferentiate. Polycomb group (PcG) proteins mediate gene silencing and repress transdifferentiation in a manner dependent on histone H3 lysine 27 trimethylation (H3K27me3). However, macrophages migrated into inflamed tissues can transdifferentiate, but it is unknown whether inflammation alters PcG-dependent silencing. Here we show that the JmjC-domain protein Jmjd3 is a H3K27me demethylase expressed in macrophages in response to bacterial products and inflammatory cytokines. Jmjd3 binds PcG target genes and regulates their H3K27me3 levels and transcriptional activity. The discovery of an inducible enzyme that erases a histone mark controlling differentiation and cell identity provides a link between inflammation and reprogramming of the epigenome, which could be the basis for macrophage plasticity and might explain the differentiation abnormalities in chronic inflammation.
表观遗传染色质标记限制了分化细胞响应环境线索改变基因表达程序以及转分化的能力。多梳蛋白家族（PcG）蛋白以依赖组蛋白H3赖氨酸27三甲基化（H3K27me3）的方式介导基因沉默并抑制转分化。然而，迁移至炎症组织的巨噬细胞能够发生转分化，但炎症是否会改变PcG依赖的沉默尚不清楚。在此，我们表明JmjC结构域蛋白Jmjd3是一种H3K27me去甲基化酶，在巨噬细胞中响应细菌产物和炎性细胞因子而表达。Jmjd3结合PcG靶基因并调节其H3K27me3水平和转录活性。一种可诱导的酶能够擦除控制分化和细胞特性的组蛋白标记，这一发现建立了炎症与表观基因组重编程之间的联系，这可能是巨噬细胞可塑性的基础，并且可能解释慢性炎症中的分化异常。
