An Osteoporosis Risk SNP at 1p36.12 Acts as an Allele-Specific Enhancer to Modulate LINC00339 Expression via Long-Range Loop Formation

被引：82

作者：

Chen, Xiao-Feng ^{[1
,2
]}

Zhu, Dong-Li ^{[1
,2
]}

Yang, Man ^{[1
]}

Hu, Wei-Xin ^{[1
]}

Duan, Yuan-Yuan ^{[1
]}

Lu, Bing-Jie ^{[1
]}

Rong, Yu ^{[1
]}

Dong, Shan-Shan ^{[1
]}

Hao, Ruo-Han ^{[1
]}

Chen, Jia-Bin ^{[1
]}

Chen, Yi-Xiao ^{[1
]}

Yao, Shi ^{[1
]}

Thynn, Hlaing Nwe ^{[1
]}

Guo, Yan ^{[1
]}

Yang, Tie-Lin ^{[1
]}

机构：

[1] Xi An Jiao Tong Univ, Sch Life Sci & Technol, Minist Educ, Key Lab Biomed Informat Engn, Xian 710049, Shaanxi, Peoples R China

[2] Xi An Jiao Tong Univ, Sch Life Sci & Technol, Inst Mol Genet, Xian 710049, Shaanxi, Peoples R China

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2018年 / 102卷 / 05期

基金：

中国博士后科学基金; 中国国家自然科学基金;

关键词：

BONE-MINERAL DENSITY; GENOME-WIDE ASSOCIATION; CHROMATIN INTERACTIONS; GENE-EXPRESSION; NONCODING RNAS; HUMAN-CELLS; COMPLEX TRAITS; LOCI; TRANSCRIPTION; DISEASE;

D O I：

10.1016/j.ajhg.2018.03.001

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Genome-wide association studies (GWASs) have reproducibly associated variants within intergenic regions of 1p36.12 locus with osteoporosis, but the functional roles underlying these noncoding variants are unknown. Through an integrative functional genomic and epigenomic analyses, we prioritized rs6426749 as a potential causal SNP for osteoporosis at 1p36.12. Dual-luciferase assay and CRISPR/ Cas9 experiments demonstrate that rs6426749 acts as a distal allele-specific enhancer regulating expression of a lncRNA (LINC00339) (similar to 360 kb) via long-range chromatin loop formation and that this loop is mediated by CTCF occupied near rs6426749 and LINC00339 promoter region. Specifically, rs6426749-G allele can bind transcription factor TFAP2A, which efficiently elevates the enhancer activity and increases LINC00339 expression. Downregulation of LINC00339 significantly increases the expression of CDC42 in osteoblast cells, which is a pivotal regulator involved in bone metabolism. Our study provides mechanistic insight into how a noncoding SNP affects osteoporosis by long-range interaction, a finding that could indicate promising therapeutic targets for osteoporosis.

引用

页码：776 / 793

页数：18

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