A ChIP-seq defined genome-wide map of vitamin D receptor binding: Associations with disease and evolution
A ChIP-seq defined genome-wide map of vitamin D receptor binding: Associations with disease and evolution
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DOI：
10.1101/gr.107920.110
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发表时间：
2010-10-01
期刊：
影响因子：
7
通讯作者：
Knight, Julian C.
中科院分区：
文献类型：
--
作者：
Ramagopalan, Sreeram V.;Heger, Andreas;Knight, Julian C.
维生素D最初被认为在钙稳态中作用有限，其在生物学中的多效性作用及其临床意义现在才逐渐显现出来。然而，维生素D通过其同源的核维生素D受体（VDR）的作用方式以及它对多种疾病的影响仍知之甚少。我们利用染色质免疫沉淀结合大规模平行DNA测序（ChIP - seq）确定了维生素D受体在整个人类基因组中的结合情况。在骨化三醇刺激后，我们确定了2776个被维生素D受体占据的基因组位置以及229个因维生素D作用而表达发生显著变化的基因。维生素D受体结合位点在全基因组关联（GWA）研究确定的自身免疫和癌症相关基因附近显著富集。具有维生素D受体结合的显著基因包括与多发性硬化症相关的IRF8，以及与克罗恩病和1型糖尿病相关的PTPN2。此外，来自全基因组关联的许多单核苷酸多态性关联直接位于维生素D受体结合区间内，例如，与系统性红斑狼疮相关的rs13385731和与1型糖尿病相关的rs947474。我们还观察到在亚洲和欧洲血统个体的正选择区域内维生素D受体区间显著富集。染色质免疫沉淀测序对转录因子结合的测定，与全基因组关联数据相结合，为进一步理解复杂疾病的分子基础提供了一种强有力的方法。
Initially thought to play a restricted role in calcium homeostasis, the pleiotropic actions of vitamin D in biology and their clinical significance are only now becoming apparent. However, the mode of action of vitamin D, through its cognate nuclear vitamin D receptor (VDR), and its contribution to diverse disorders, remain poorly understood. We determined VDR binding throughout the human genome using chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq). After calcitriol stimulation, we identified 2776 genomic positions occupied by the VDR and 229 genes with significant changes in expression in response to vitamin D. VDR binding sites were significantly enriched near autoimmune and cancer associated genes identified from genome-wide association (GWA) studies. Notable genes with VDR binding included IRF8, associated with MS, and PTPN2 associated with Crohn's disease and T1D. Furthermore, a number of single nucleotide polymorphism associations from GWA were located directly within VDR binding intervals, for example, rs13385731 associated with SLE and rs947474 associated with T1D. We also observed significant enrichment of VDR intervals within regions of positive selection among individuals of Asian and European descent. ChIP-seq determination of transcription factor binding, in combination with GWA data, provides a powerful approach to further understanding the molecular bases of complex diseases.