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首页> 外文期刊>Human Genetics >Interaction between genetic and epigenetic variation defines gene expression patterns at the asthma-associated locus 17q12-q21 in lymphoblastoid cell lines
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Interaction between genetic and epigenetic variation defines gene expression patterns at the asthma-associated locus 17q12-q21 in lymphoblastoid cell lines

机译：遗传变异与表观遗传变异之间的相互作用定义了成淋巴细胞样细胞系中与哮喘相关的基因座17q12-q21的基因表达模式

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摘要

Phenotypic variation results from variation in gene expression, which is modulated by genetic and/or epigenetic factors. To understand the molecular basis of human disease, interaction between genetic and epigenetic factors needs to be taken into account. The asthma-associated region 17q12-q21 harbors three genes, the zona pellucida binding protein 2 (ZPBP2), gasdermin B (GSDMB) and ORM1-like 3 (ORMDL3), that show allele-specific differences in expression levels in lymphoblastoid cell lines (LCLs) and CD4+ T cells. Here, we report a molecular dissection of allele-specific transcriptional regulation of the genes within the chromosomal region 17q12-q21 combining in vitro transfection, formaldehyde-assisted isolation of regulatory elements, chromatin immunoprecipitation and DNA methylation assays in LCLs. We found that a single nucleotide polymorphism rs4795397 influences the activity of ZPBP2 promoter in vitro in an allele-dependent fashion, and also leads to nucleosome repositioning on the asthma-associated allele. However, variable methylation of exon 1 of ZPBP2 masks the strong genetic effect on ZPBP2 promoter activity in LCLs. In contrast, the ORMDL3 promoter is fully unmethylated, which allows detection of genetic effects on its transcription. We conclude that the cis-regulatory effects on 17q12-q21 gene expression result from interaction between several regulatory polymorphisms and epigenetic factors within the cis-regulatory haplotype region.
机译：表型变异是由基因表达的变异引起的，其受遗传和/或表观遗传因素调节。为了了解人类疾病的分子基础，需要考虑遗传因素与表观遗传因素之间的相互作用。与哮喘相关的区域17q12-q21包含三个基因，即透明带结合蛋白2（ZPBP2），加德明B（GSDMB）和ORM1样3（ORMDL3），它们在淋巴母细胞样细胞系中显示出等位基因特异性差异（ LCL）和CD4 + T细胞。在这里，我们报告了在染色体区域17q12-q21内结合体外转染，甲醛辅助分离的调控元件，染色质免疫沉淀和LCL中的DNA甲基化分析等位基因特异性转录调控的基因的分子解剖。我们发现单核苷酸多态性rs4795397以等位基因依赖的方式影响ZPBP2启动子的体外活性，并且还导致与哮喘相关的等位基因上的核小体重新定位。但是，ZPBP2外显子1的可变甲基化掩盖了LCL中ZPBP2启动子活性的强大遗传效应。相比之下，ORMDL3启动子是完全未甲基化的，从而可以检测其转录的遗传效应。我们得出的结论是，对17q12-q21基因表达的顺式调节作用是由几个调节多态性与顺式调节单倍型区域内的表观遗传因子之间的相互作用引起的。

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