对肝组织的研究确定了与基因表达、2 型糖尿病和其他代谢性疾病相关的功能基因调控元件。
Studies of liver tissue identify functional gene regulatory elements associated to gene expression, type 2 diabetes, and other metabolic diseases.
机构信息
Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Department of Cell and Molecular Biology, Computational Biology and Bioinformatics, Uppsala University, Uppsala, Sweden.
出版信息
Hum Genomics. 2019 Apr 29;13(1):20. doi: 10.1186/s40246-019-0204-8.
BACKGROUND
Genome-wide association studies (GWAS) of diseases and traits have found associations to gene regions but not the functional SNP or the gene mediating the effect. Difference in gene regulatory signals can be detected using chromatin immunoprecipitation and next-gen sequencing (ChIP-seq) of transcription factors or histone modifications by aligning reads to known polymorphisms in individual genomes. The aim was to identify such regulatory elements in the human liver to understand the genetics behind type 2 diabetes and metabolic diseases.
METHODS
The genome of liver tissue was sequenced using 10X Genomics technology to call polymorphic positions. Using ChIP-seq for two histone modifications, H3K4me3 and H3K27ac, and the transcription factor CTCF, and our established bioinformatics pipeline, we detected sites with significant difference in signal between the alleles.
RESULTS
We detected 2329 allele-specific SNPs (AS-SNPs) including 25 associated to GWAS SNPs linked to liver biology, e.g., 4 AS-SNPs at two type 2 diabetes loci. Two hundred ninety-two AS-SNPs were associated to liver gene expression in GTEx, and 134 AS-SNPs were located on 166 candidate functional motifs and most of them in EGR1-binding sites.
CONCLUSIONS
This study provides a valuable collection of candidate liver regulatory elements for further experimental validation.
背景
疾病和特征的全基因组关联研究（GWAS）已经发现了与基因区域的关联，但没有发现功能 SNP 或介导效应的基因。通过将读取与个体基因组中的已知多态性对齐，可以使用转录因子或组蛋白修饰的染色质免疫沉淀和下一代测序（ChIP-seq）来检测基因调控信号的差异。目的是在人类肝脏中识别这种调节元件，以了解 2 型糖尿病和代谢疾病背后的遗传学。
方法
使用 10X Genomics 技术对肝脏组织的基因组进行测序，以调用多态性位置。使用 ChIP-seq 进行两种组蛋白修饰（H3K4me3 和 H3K27ac）和转录因子 CTCF，并使用我们建立的生物信息学管道，我们检测到了等位基因之间信号有显著差异的位点。
结果
我们检测到了 2329 个等位基因特异性 SNP（AS-SNPs），包括 25 个与 GWAS SNP 相关的与肝脏生物学相关的 SNP，例如，两个 2 型糖尿病位点的 4 个 AS-SNPs。292 个 AS-SNPs 与 GTEx 中的肝脏基因表达相关，134 个 AS-SNPs 位于 166 个候选功能基序上，其中大多数位于 EGR1 结合位点上。
结论
这项研究为进一步的实验验证提供了有价值的候选肝脏调节元件集合。
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