School of Medicine, Institute of Biomedicine, University of Eastern Finland, FI-70211 Kuopio, Finland.
School of Medicine, Institute of Biomedicine, University of Eastern Finland, FI-70211 Kuopio, Finland.
Biochim Biophys Acta Gene Regul Mech. 2018 Aug;1861(8):697-705. doi: 10.1016/j.bbagrm.2018.05.006. Epub 2018 Jul 3.
The micronutrient vitamin D significantly modulates the human epigenome via enhancing genome-wide the rate of accessible chromatin and vitamin D receptor (VDR) binding. This study focuses on histone marks of active chromatin at promoter and enhancer regions and investigates, whether these genomic loci are sensitive to vitamin D. The epigenome of THP-1 human monocytes contains nearly 23,000 sites with H3K4me3 histone modifications, 550 of which sites are significantly (p < 0.05) modulated by stimulation with the VDR ligand 1α,25-dihydroxyvitamin D (1,25(OH)D). H3K27ac histone modifications mark active chromatin and 2473 of 45,500 sites are vitamin D sensitive. The two types of ligand-dependent histone marks allow to distinguish promoter and enhancer regulation by vitamin D, respectively. Transcription start site overlap is the prime attribute of ligand-dependent H3K4me3 marks, while VDR co-location is the top ranking parameter describing 1,25(OH)D-sensitive H3K27ac marks at enhancers. A categorization of 1,25(OH)D-sensitive histone marks by machine learning algorithms - using the attributes overall peak strength and ligand inducibility - highlights 260 and 287 regions with H3K4me3 and H3K27ac modifications, respectively. These loci are found at the promoter regions of 59 vitamin D target genes and their associated enhancers. In this way, ligand-dependent histone marks provide a link of the effects of 1,25(OH)D on the epigenome with previously reported mRNA expression changes of vitamin D target genes. In conclusion, the human epigenome responds also on the level of histone modifications to 1,25(OH)D stimulation. This allows a more detailed understanding of vitamin D target gene regulation.
微量营养素维生素 D 通过增强全基因组可及染色质和维生素 D 受体 (VDR) 结合的速率，显著调节人类表观基因组。本研究专注于启动子和增强子区域的活性染色质组蛋白标记，并研究这些基因组位点是否对维生素 D 敏感。THP-1 人单核细胞的表观基因组包含近 23000 个具有 H3K4me3 组蛋白修饰的位点，其中 550 个位点受 VDR 配体 1α,25-二羟维生素 D（1,25(OH)D）刺激的显著调节（p < 0.05）。H3K27ac 组蛋白修饰标记活性染色质，其中 45500 个位点中有 2473 个对维生素 D 敏感。两种类型的配体依赖性组蛋白标记分别允许区分维生素 D 的启动子和增强子调节。转录起始位点重叠是配体依赖性 H3K4me3 标记的主要属性，而 VDR 共定位是描述增强子上 1,25(OH)D 敏感 H3K27ac 标记的顶级参数。使用属性整体峰强度和配体诱导性，通过机器学习算法对 1,25(OH)D 敏感的组蛋白标记进行分类，突出了分别具有 H3K4me3 和 H3K27ac 修饰的 260 和 287 个区域。这些位点位于 59 个维生素 D 靶基因的启动子区域及其相关增强子。通过这种方式，配体依赖性组蛋白标记将 1,25(OH)D 对表观基因组的影响与先前报道的维生素 D 靶基因的 mRNA 表达变化联系起来。总之，人类表观基因组也会对 1,25(OH)D 刺激的组蛋白修饰水平做出反应。这使得对维生素 D 靶基因调控的理解更加详细。
