The Association Between Vitamin D and Multiple Sclerosis Risk: 1,25(OH)2D3 Induces Super-Enhancers Bound by VDR
The Association Between Vitamin D and Multiple Sclerosis Risk: 1,25(OH)2D3 Induces Super-Enhancers Bound by VDR
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DOI：
10.3389/fimmu.2019.00488
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发表时间：
2019-03-19
影响因子：
7.3
通讯作者：
Korner, Heinrich
中科院分区：
文献类型：
--
作者：
Lu, Ming;McComish, Bennet J.;Korner, Heinrich
超级增强子 (SE) 是一组具有相对高密度的特定染色质特征的增强子。 SE 通常调节可以决定细胞身份和分化的关键基因。识别 SE 及其影响对于预测关键调控基因（例如主转录因子基因或癌基因）可能至关重要。信号诱导 SE 是信号末端转录因子 (TF) 结合区域的密集区域，可以调节多发性硬化症 (MS) 等复杂疾病中环境因素（例如维生素 D）和遗传因素（即风险变异）之间的相互作用。作为一种复杂的自身免疫性疾病，MS 的病因和进展，包括维生素 D 和 MS 风险变异之间的相互作用，仍不清楚，可以从信号 SE 方面进行探索。维生素 D [其活性形式：1,25(OH)(2)D-3] 是 MS 的一个环境风险因素。它结合维生素 D 受体 (VDR) 并调节基因表达。本研究探讨了 VDR 超级增强子 (VSE) 与 MS 风险变异之间的关联。首先，我们重新分析公共 ChIP-seq 和 RNA-seq 数据，根据 VSE 的持久性和次级 VDR 结合的组合将 VSE 分为三类。其次，我们指出具有靠近 MS 风险变异的 VSE 区域的基因。此外，我们发现 MS 风险变异在 VSE 区域富集，并且我们指出了一些具有 VSE 重叠 MS 风险变异的基因以供进一步探索。我们还从一组基因中发现了两个基因簇，显示出与 MS 风险基因 ZMIZ1 的表达模式相关，这些基因似乎受到 THP-1 细胞中 VSE 的调节。这是首次对 VSE 进行分析，我们基于 VSE 直接将 MS 风险的遗传风险因素与维生素 D 联系起来。
A super-enhancer (SE) is a cluster of enhancers with a relatively high density of particular chromatin features. SEs typically regulate key genes that can determine cell identity and differentiation. Identifying SEs and their effects may be critical in predicting key regulatory genes, such as master transcription factor genes or oncogenes. Signal inducible SEs are dense stretches of signal terminal transcription factor (TF) binding regions, and may modulate the interaction between environmental factors (e.g., Vitamin D) and genetic factors (i.e., risk variants) in complex diseases such as multiple sclerosis (MS). As a complex autoimmune disease, the etiology and progression of MS, including the interaction between Vitamin D and MS risk variants, is still unclear and can be explored from the aspect of signal SEs. Vitamin D [with its active form: 1,25(OH)(2)D-3], is an environmental risk factor for MS. It binds the Vitamin D receptor (VDR) and regulates gene expression. This study explores the association between VDR super-enhancers (VSEs) and MS risk variants. Firstly, we reanalyse public ChIP-seq and RNA-seq data to classify VSEs into three categories according to their combinations of persistent and secondary VDR binding. Secondly, we indicate the genes with VSE regions that are near MS risk variants. Furthermore, we find that MS risk variants are enriched in VSE regions, and we indicate some genes with a VSE overlapping MS risk variant for further exploration. We also find two clusters of genes from the set of genes showing correlation of expression patterns with the MS risk gene ZMIZ1 that appear to be regulated by VSEs in THP-1 cells. It is the first time that VSEs have been analyzed, and we directly connect the genetic risk factors for MS risk with Vitamin D based on VSEs.