Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Nat Genet. 2010 Mar;42(3):255-9. doi: 10.1038/ng.530. Epub 2010 Jan 31.
Tissue-specific transcriptional regulation is central to human disease. To identify regulatory DNA active in human pancreatic islets, we profiled chromatin by formaldehyde-assisted isolation of regulatory elements coupled with high-throughput sequencing (FAIRE-seq). We identified approximately 80,000 open chromatin sites. Comparison of FAIRE-seq data from islets to that from five non-islet cell lines revealed approximately 3,300 physically linked clusters of islet-selective open chromatin sites, which typically encompassed single genes that have islet-specific expression. We mapped sequence variants to open chromatin sites and found that rs7903146, a TCF7L2 intronic variant strongly associated with type 2 diabetes, is located in islet-selective open chromatin. We found that human islet samples heterozygous for rs7903146 showed allelic imbalance in islet FAIRE signals and that the variant alters enhancer activity, indicating that genetic variation at this locus acts in cis with local chromatin and regulatory changes. These findings illuminate the tissue-specific organization of cis-regulatory elements and show that FAIRE-seq can guide the identification of regulatory variants underlying disease susceptibility.
组织特异性转录调控是人类疾病的核心。为了鉴定在人胰岛中活跃的调控 DNA，我们通过甲醛辅助的调控元件分离与高通量测序（FAIRE-seq）对染色质进行了分析。我们鉴定出了大约 80000 个开放染色质位点。将来自胰岛的 FAIRE-seq 数据与来自五个人类非胰岛细胞系的数据进行比较，揭示了大约 3300 个物理连接的胰岛选择性开放染色质位点簇，这些簇通常包含胰岛特异性表达的单个基因。我们将序列变异映射到开放染色质位点上，并发现与 2 型糖尿病强烈相关的 TCF7L2 内含子变体 rs7903146 位于胰岛选择性开放染色质中。我们发现，携带 rs7903146 杂合子的人胰岛样本在胰岛 FAIRE 信号中表现出等位基因失衡，并且该变体改变了增强子活性，表明该基因座的遗传变异与局部染色质和调控变化顺式作用。这些发现阐明了顺式调控元件的组织特异性组织，并表明 FAIRE-seq 可以指导鉴定疾病易感性相关的调控变异。
