Genome-scale Capture C promoter interactions implicate effector genes at GWAS loci for bone mineral density
Genome-scale Capture C promoter interactions implicate effector genes at GWAS loci for bone mineral density
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DOI：
10.1038/s41467-019-09302-x
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发表时间：
2019-03-19
影响因子：
16.6
通讯作者：
Grant, Struan F. A.
中科院分区：
文献类型：
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作者：
Chesi, Alessandra;Wagley, Yadav;Grant, Struan F. A.
骨质疏松症是一种具有重要遗传成分的毁灭性疾病。GWAS已经发现了与骨矿物质密度（BMD）密切相关的遗传信号，但没有发现效应基因的精确定位。在这里，我们在人类间充质祖细胞衍生的成骨细胞中进行物理和直接的变异基因定位，采用大规模平行的、高分辨率的基于Capture C的方法，以同时表征所有人类启动子的全基因组相互作用。通过交叉我们的Capture C和ATAC-seq数据，我们观察到候选因果变异和开放染色质中假定的靶基因启动子之间的一致联系，在所调查的273个BMD位点中，约有17%。两个新的相关基因，‘CPED1-WNT16’的ING3和‘STARD3NL’的EPDR1的敲低，抑制成骨细胞的形成，同时促进脂肪的形成。因此，这种方法有助于发现骨质疏松症的靶点，这里以两个参与决定间充质祖细胞命运的相关基因为例，并可应用于其他常见遗传疾病。
Osteoporosis is a devastating disease with an essential genetic component. GWAS have discovered genetic signals robustly associated with bone mineral density (BMD), but not the precise localization of effector genes. Here, we carry out physical and direct variant to gene mapping in human mesenchymal progenitor cell-derived osteoblasts employing a massively parallel, high resolution Capture C based method in order to simultaneously characterize the genome-wide interactions of all human promoters. By intersecting our Capture C and ATAC-seq data, we observe consistent contacts between candidate causal variants and putative target gene promoters in open chromatin for similar to 17% of the 273 BMD loci investigated. Knockdown of two novel implicated genes, ING3 at 'CPED1-WNT16' and EPDR1 at 'STARD3NL', inhibits osteoblastogenesis, while promoting adipogenesis. This approach therefore aids target discovery in osteoporosis, here on the example of two relevant genes involved in the fate determination of mesenchymal progenitors, and can be applied to other common genetic diseases.