Molecular endocrinology of vitamin D on the epigenome level
Molecular endocrinology of vitamin D on the epigenome level
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DOI：
10.1016/j.mce.2017.03.016
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发表时间：
2017-09-15
影响因子：
4.1
通讯作者：
Carlberg, Carsten
中科院分区：
文献类型：
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作者：
Carlberg, Carsten
维生素D的分子内分泌学基于以下事实：i）其代谢物1 α，25-二羟基维生素D-3（1，25（OH）（2）D-3）是核受体维生素D受体（VDR）的高亲和力配体，ii）转录因子VDR是细胞核中1，25（OH）（2）D-3的独特靶点。表观基因组的短期改变主要是核小体形成组蛋白的翻译后修饰状态的变化，其结果是i）染色质可及性的局部增加或减少和ii）基因转录的激活或抑制。维生素D通过VDR对数百个主要靶基因的表达具有直接影响，这意味着对表观基因组的许多影响。下一代测序方法，如ChIP-seq和FAIRE-seq，应用于维生素D信号传导的细胞模型系统，如THP-1人单核细胞，并为维生素D信号传导的染色质模型提供数据。该模型的关键点是i）在不存在配体的情况下，VDR结合至可接近的染色质内的有限数目的基因座，ii）用配体刺激增加DNA结合的VDR分子的数目，iii）VDR对基因组DNA的接近由先锋因子（例如单核细胞中的PU.1）支持，iv）VDR结合导致染色质的局部开放，和v）拓扑关联结构域锚形成CCCTC-1的结合强度主要VDR结合位点上游和下游的结合因子位点响应于配体刺激而改变。该模型提供了维生素D分子内分泌学的现有基础，并且将来将通过整合维生素D敏感的染色质标记物和其他全基因组数据（例如辅助因子、染色质修饰酶和染色质重塑蛋白的1，25（OH）（2）D-3敏感结合）来完善。(C)2017爱思唯尔B. V.保留所有权利。
The molecular endocrinology of vitamin D is based on the facts that i) its metabolite 1 alpha,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) is the high affinity ligand of the nuclear receptor vitamin D receptor (VDR) and ii) the transcription factor VDR is the unique target of 1,25(OH)(2)D-3 in the nucleus. Shortterm alterations of the epigenome are primarily changes in the post-translational modification status of nucleosome-forming histone proteins, the consequences of which are i) a local increase or decrease in chromatin accessibility and ii) the activation or repression of gene transcription. Vitamin D has via VDR a direct effect on the expression of several hundred primary target genes implying numerous effects on the epigenome. Next-generation sequencing methods, such as ChIP-seq and FAIRE-seq, were applied to cellular model systems of vitamin D signaling, such as THP-1 human monocytes, and provided data for a chromatin model of vitamin D signaling. Key points of this model are that i) in the absence of ligand VDR binds to a limited number of loci within accessible chromatin, ii) a stimulation with ligand increases the number of DNA-bound VDR molecules, iii) VDR's access to genomic DNA is supported by pioneer factors, such as PU.1 in monocytes, iv) VDR binding leads to local opening of chromatin and v) the binding strength of topologically associating domain anchor forming CCCTC-binding factor sites upstream and downstream of prominent VDR binding sites is changing in response to ligand stimulation. This model provides the present basis of the molecular endocrinology of vitamin D and will be in future refined by the integration of vitamin D-sensitive chromatin markers and other genome-wide data, such as the 1,25(OH)(2)D-3-sensitive binding of co-factors, chromatin modifying enzymes and chromatin remodeling proteins. (C) 2017 Elsevier B.V. All rights reserved.