Institute of Biochemistry I - Pathobiochemistry/ZAFES, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Cytokine. 2011 Feb;53(2):256-62. doi: 10.1016/j.cyto.2010.11.002. Epub 2010 Dec 4.
Epigenetic processes elicit changes in gene expression by modifying DNA bases or histone side chains without altering DNA sequences. Recently discovered Jumonji histone demethylases (JHDMs) affect gene expression by demethylating lysine residues of histone tails. JHDMs belong to a family of dioxygenases and share similarities with prolyl hydroxylases (PHDs). Therefore, we investigated the influence of hypoxia in macrophages on histone methylation. All JHDM family members JMJD1A-C and JMJD2A-D are expressed in macrophages. Thus, we analyzed the methylation status of histone H3 residues not only under hypoxia but also after treatment with the dioxygenase-inhibitors DMOG, NO and ROS. Western analysis revealed increased methylations in H3K9me2/me3 and H3K36me3 at pO₂ below 3%, DMOG, NO and ROS treatment. Chromatin immunoprecipitation (ChIP) assays demonstrated increased repressive marks H3K9me2 and H3K9me3 in specific promoter regions of the chemokine Ccl2 and the chemokine receptors Ccr1 and Ccr5, which correlated with a downregulation of their mRNA expression under hypoxic conditions. In contrasts, the hypoxia-inducible factor (HIF) target gene adrenomedullin (ADM) mRNA was upregulated and no increase in its histone modification was observed. We suggest that hypoxia and a concomitant loss of JHDM activity increases H3K9 methylation and decreases chemokine expression.
表观遗传过程通过修饰 DNA 碱基或组蛋白侧链而不改变 DNA 序列来引起基因表达的变化。最近发现的 Jumonji 组蛋白去甲基酶（JHDM）通过去甲基化组蛋白尾部赖氨酸残基来影响基因表达。JHDM 属于双加氧酶家族，与脯氨酰羟化酶（PHD）具有相似性。因此，我们研究了巨噬细胞中的缺氧对组蛋白甲基化的影响。所有 JHDM 家族成员 JMJD1A-C 和 JMJD2A-D 在巨噬细胞中表达。因此，我们不仅在缺氧条件下，而且在二氧酶抑制剂 DMOG、NO 和 ROS 处理后，分析了组蛋白 H3 残基的甲基化状态。Western 分析显示，在 pO₂低于 3%、DMOG、NO 和 ROS 处理下，H3K9me2/me3 和 H3K36me3 的甲基化增加。染色质免疫沉淀（ChIP）实验表明，在趋化因子 Ccl2 和趋化因子受体 Ccr1 和 Ccr5 的特定启动子区域，H3K9me2 和 H3K9me3 的抑制性标记增加，这与它们在缺氧条件下的 mRNA 表达下调相关。相比之下，缺氧诱导因子（HIF）靶基因肾上腺髓质素（ADM）的 mRNA 上调，并且其组蛋白修饰没有增加。我们认为，缺氧和伴随的 JHDM 活性丧失增加了 H3K9 甲基化并降低了趋化因子的表达。
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