Enhancer variants associated with Alzheimer's disease affect gene expression via chromatin looping
Enhancer variants associated with Alzheimer's disease affect gene expression via chromatin looping
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DOI：
10.1186/s12920-019-0574-8
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发表时间：
2019-09-09
影响因子：
2.7
通讯作者：
Nakaya, Akihiro
中科院分区：
文献类型：
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作者：
Kikuchi, Masataka;Hara, Norikazu;Nakaya, Akihiro
全基因组关联研究（GWASs）已经确定了可能是阿尔茨海默病（AD）遗传因素的单核苷酸多态性（snp）。然而，这些AD相关的snp （AD snp）是如何促成这种疾病的发病机制尚不清楚，因为它们大多数位于非编码区，如内含子和基因间区。先前的研究报道了一些疾病相关的snp影响包括增强子在内的调控元件。我们假设非编码AD snp位于增强子中，并通过染色质环影响基因表达水平。方法从GWAS目录数据库中提取GWAS p值小于1.00 × 10（- 6）的406个AD snp，对非编码区AD snp进行表征。其中，我们在非编码区选择了392个snp。接下来，我们利用127种人类组织或细胞类型中预测的增强子的公开数据，检查这些非编码AD snp是否位于通常调节基因表达水平的增强子中。我们在增强子中寻找受非编码AD snp影响的表达数量性状位点（eQTL）基因，因为增强子是影响基因表达水平的调控元件。为了阐明增强子内的非编码AD单核苷酸多态性如何影响基因表达水平，我们通过Hi-C实验鉴定了染色质-染色质相互作用。结果研究发现：(1)近30%的非编码AD snp位于增强子中；(2)受增强子内非编码AD snp影响的eQTL基因与淀粉样蛋白清除、突触传递和免疫反应相关；(3) 95%位于增强子上的AD snp与其eQTL基因在拓扑相关区域共定位，表明调控可能通过染色质高阶结构发生；(4) rs1476679通过CTCF-CTCF相互作用在空间上联系eQTL基因的启动子；(5)其他AD snp如rs7364180的作用可能至少部分是间接通过调控转录因子来调控AD相关基因。结论非编码AD snp可能影响增强子的功能，从而通过染色质环影响周围或远端基因的表达水平。这一结果可能解释了一些非编码AD snp如何参与AD的发病机制。
Background Genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms (SNPs) that may be genetic factors underlying Alzheimer's disease (AD). However, how these AD-associated SNPs (AD SNPs) contribute to the pathogenesis of this disease is poorly understood because most of them are located in non-coding regions, such as introns and intergenic regions. Previous studies reported that some disease-associated SNPs affect regulatory elements including enhancers. We hypothesized that non-coding AD SNPs are located in enhancers and affect gene expression levels via chromatin loops. Methods To characterize AD SNPs within non-coding regions, we extracted 406 AD SNPs with GWAS p-values of less than 1.00 x 10(- 6) from the GWAS catalog database. Of these, we selected 392 SNPs within non-coding regions. Next, we checked whether those non-coding AD SNPs were located in enhancers that typically regulate gene expression levels using publicly available data for enhancers that were predicted in 127 human tissues or cell types. We sought expression quantitative trait locus (eQTL) genes affected by non-coding AD SNPs within enhancers because enhancers are regulatory elements that influence the gene expression levels. To elucidate how the non-coding AD SNPs within enhancers affect the gene expression levels, we identified chromatin-chromatin interactions by Hi-C experiments. Results We report the following findings: (1) nearly 30% of non-coding AD SNPs are located in enhancers; (2) eQTL genes affected by non-coding AD SNPs within enhancers are associated with amyloid beta clearance, synaptic transmission, and immune responses; (3) 95% of the AD SNPs located in enhancers co-localize with their eQTL genes in topologically associating domains suggesting that regulation may occur through chromatin higher-order structures; (4) rs1476679 spatially contacts the promoters of eQTL genes via CTCF-CTCF interactions; (5) the effect of other AD SNPs such as rs7364180 is likely to be, at least in part, indirect through regulation of transcription factors that in turn regulate AD associated genes. Conclusion Our results suggest that non-coding AD SNPs may affect the function of enhancers thereby influencing the expression levels of surrounding or distant genes via chromatin loops. This result may explain how some non-coding AD SNPs contribute to AD pathogenesis.