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首页> 外文期刊>Journal of Molecular Biology >Calcitriol upregulates open chromatin and elongation markers at functional vitamin D response elements in the distal part of the 5-lipoxygenase gene.
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Calcitriol upregulates open chromatin and elongation markers at functional vitamin D response elements in the distal part of the 5-lipoxygenase gene.

机译：骨化三醇上调5-脂氧合酶基因远端的功能性维生素D反应元件上的开放染色质和延伸标记。

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摘要

5-Lipoxygenase (5-LO) gene expression is strongly upregulated during induction of myeloid cell differentiation by 1alpha,25-dihydroxyvitamin D(3) (calcitriol) and transforming growth factor-beta (TGFbeta) in a promoter-independent manner. In an activity-guided approach using reporter gene assays where the distal part of the 5-LO gene was included in the reporter gene plasmid, we localized vitamin D response elements (VDREs) within exon 10, exon 12, and intron M. We found that these newly identified VDRE sites are bound by vitamin D receptor both in vitro by gel-shift analysis and in vivo by chromatin immunoprecipitation assays. In reporter gene assays, the distal part of the 5-LO gene has promoter-like activity that is inducible by calcitriol in a vitamin D receptor-dependent manner. The vitamin D effects were attenuated when the VDREs in exon 10, exon 12, and intron M were deleted or mutated. When we analyzed the effects of calcitriol plus TGFbeta on chromatin modifications at exon 10, exon 12, and intron M of the 5-LO gene in Mono Mac 6 cells by chromatin immunoprecipitation analysis, we found an increase in histone H4 K20 monomethylation and a prominent presence of histone H3 K36 trimethylation. Combined treatment with calcitriol and TGFbeta also increased histone H4 acetylation, a marker for open chromatin, and the elongation form of RNA polymerase II at these sites, whereas the transcription initiation marker histone H3 K4 trimethylation was almost undetectable. The data suggest that calcitriol induces chromatin opening and transcript elongation via VDREs located at the 3'-end of the 5-LO gene.
机译：5-Lipoxygenase（5-LO）基因表达在髓细胞分化诱导过程中被1alpha，25-dihydroxyvitamin D（3）（calcitriol）和转化生长因子-β（TGFbeta）以启动子独立的方式强烈上调。在使用报道基因试验的活动指导方法中，将5-LO基因的远端包括在报道基因质粒中，我们将维生素D反应元件（VDRE）定位在第10外显子，第12外显子和内含子M内。这些新发现的VDRE位点在体外通过凝胶移位分析和在体内通过染色质免疫沉淀分析均与维生素D受体结合。在报告基因分析中，5-LO基因的远端部分具有启动子样活性，该钙三醇可以维生素D受体依赖性方式诱导启动子样活性。当外显子10，外显子12和内含子M中的VDRE缺失或突变时，维生素D的作用减弱。当我们通过染色质免疫沉淀分析分析骨化三醇加TGFβ对Mono Mac 6细胞中外显子10，外显子12和5-LO基因的内含子M染色质修饰的影响时，我们发现组蛋白H4 K20单甲基化增加并且显着组蛋白H3 K36三甲基化的存在。骨化三醇和TGFbeta的联合处理还增加了组蛋白H4乙酰化，开放染色质的标志物和这些位置处RNA聚合酶II的延长形式，而转录起始标志物组蛋白H3 K4三甲基化几乎是不可检测的。数据表明骨化三醇通过位于5-LO基因3'端的VDRE诱导染色质开放和转录本延长。

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