全基因组捕获 C 启动子相互作用提示 GWAS 骨密度位点的效应基因。

Genome-scale Capture C promoter interactions implicate effector genes at GWAS loci for bone mineral density.

机构信息

Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, 19104, PA, USA.

Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, 48109, MI, USA.

出版信息

Nat Commun. 2019 Mar 19;10(1):1260. doi: 10.1038/s41467-019-09302-x.

DOI:10.1038/s41467-019-09302-x

PMID:30890710

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6425012/

Abstract

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 ~ 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.

摘要

骨质疏松症是一种破坏性疾病，其根本原因是遗传因素。全基因组关联研究发现了与骨密度（BMD）显著相关的遗传信号，但未能确定效应基因的确切位置。在这里，我们采用大规模平行、高分辨率的基于 Capture C 的方法，在人类间充质祖细胞衍生的成骨细胞中进行物理和直接变体到基因的映射，以便同时描述全基因组范围内所有人类启动子的相互作用。通过交叉分析我们的 Capture C 和 ATAC-seq 数据，我们观察到在开放染色质中，约 17%的 273 个 BMD 位点的候选因果变异与潜在靶基因启动子之间存在一致的接触。下调两个新发现的基因，ING3 在“CPED1-WNT16”和 EPDR1 在“STARD3NL”，可抑制成骨细胞生成，同时促进脂肪生成。因此，这种方法有助于骨质疏松症的靶点发现，以两个涉及间充质祖细胞命运决定的相关基因为例，并且可以应用于其他常见的遗传疾病。