In vivo response of the human epigenome to vitamin D: A Proof-of-principle study
In vivo response of the human epigenome to vitamin D: A Proof-of-principle study
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DOI：
10.1016/j.jsbmb.2018.01.002
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发表时间：
2018-06-01
影响因子：
4.1
通讯作者：
Neme, Antonio
中科院分区：
文献类型：
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作者：
Carlberg, Carsten;Seuter, Sabine;Neme, Antonio
体外细胞培养研究表明，激素形式的维生素D-3，Lα，25-二羟基维生素D-3，显著(p<；0.05)在数千个基因组座位上影响人类表观基因组。VitDbol维生素D干预试验(NCT02063334)的第二阶段涉及对一个人的原则验证研究，该人每28天服用三次口服维生素D-3(2000微克)。在每次补充前以及1天和2天后直接采集血样，在没有进一步体外培养的情况下从外周血单个核细胞中分离染色质，并在所有9个时间点应用FAIRE-SEQ(甲醛辅助分离调节元件测序)来评估表观基因组全染色质的可及性。维生素D-3组1天和2天血中25-羟基维生素D-3(25(OH)D-3)浓度分别平均升高11.9和19.4 nM。在5 205个基因组座位上检测到一致可及染色质，其中最显著的853个用自组织映射算法划分为早期、延迟和无响应基因组区域：70个座位在1天后已经显示，361个位置在2天后显著地(p<；0.0001)打开或关闭。有趣的是，超过一半的基因组区域与转录起始点重叠，但这些位置染色质可及性的变化对转录组没有直接影响。一些维生素D敏感的染色质部位聚集在人类基因组中的特定位置，其中最突出的是6号染色体上的人类白细胞抗原区。总之，这项研究表明，在活体条件下，25(OH)D-3血清水平相当轻微的上升足以导致人类白细胞表观基因组内数百个部位的显著变化。
In vitro cell culture studies showed that the hormonal form of vitamin D-3, l alpha,25-dihydroxyvitamin D-3, significantly (p < 0.05) affects the human epigenome at thousands of genomic loci. Phase II of the VitDbol vitamin D intervention trial (NCT02063334) involved a proof-of-principle study of one individual, who was exposed three times every 28 days to an oral bolus (2000 mu g) of vitamin D-3. Blood samples were taken directly before each supplementation as well as one and two days after, chromatin was isolated from peripheral blood mononuclear cells without any further in vitro culture and at all nine time points epigenome-wide chromatin accessibility was assessed by applying FAIRE-seq (formaldehyde -assisted isolation of regulatory elements sequencing). The vitamin D-3 bolus resulted in an average raise in 25-hydroxyvitamin D-3 (25(OH)D-3) serum concentration of 11.9 and 19.4 nM within one and two days, respectively. Consistently accessible chromatin was detected at 5205 genomic loci, the 853 most prominent of which a self-organizing map algorithm classified into early, delayed and non-responding genomic regions: 70 loci showed already after one day and 361 sites after two days significant (p < 0.0001) chromatin opening or closing. Interestingly, more than half of these genomic regions overlap with transcription start sites, but the change of chromatin accessibility at these sites has no direct effect on the transcriptome. Some of the vitamin D responsive chromatin sites cluster at specific loci within the human genome, the most prominent of which is the human leukocyte antigen region in chromosome 6. In conclusion, this study demonstrates that under in vivo conditions a rather minor rise in 25(OH)D-3 serum levels is sufficient to result in significant changes at hundreds of sites within the epigenome of human leukocytes.