A novel CpG island set identifies tissue-specific methylation at developmental gene loci.
A novel CpG island set identifies tissue-specific methylation at developmental gene loci.
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DOI：
10.1371/journal.pbio.0060022
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发表时间：
2008-01
期刊：
影响因子：
9.8
通讯作者：
Bird A
中科院分区：
文献类型：
--
作者：
Illingworth R;Kerr A;Desousa D;Jørgensen H;Ellis P;Stalker J;Jackson D;Clee C;Plumb R;Rogers J;Humphray S;Cox T;Langford C;Bird A
CpG岛是一组密集的CpG序列簇，位于CpG缺陷的人类基因组中，并与许多基因启动子相关。由于CGI与普通染色体DNA的不同之处在于它们经常缺乏胞嘧啶甲基化，我们设计了一种基于非甲基化CpG亲和层析的CGI富集法。对得到的文库进行了测序，以定义一个新的人类血液CGI集，其中包括许多当前算法无法检测到的内容。大约一半的CGI与注释的基因转录起始点有关，其余的是基因内或基因间的。使用一个代表17,000多个CGI的阵列，我们建立了6%-8%的CGI在人类血液、脑、肌肉和脾的基因组DNA中甲基化。基因间和基因内的CGI更容易发生甲基化。显示组织特异性甲基化的CGI在许多对发育至关重要的遗传位点上过度表达，包括HOX和PAX家族成员。这一发现使得全面分析CGI甲基化在正常和疾病人类组织中所起的作用成为可能。人类基因组包含大约22,000个基因，每个基因编码一种人类生命所需的蛋白质。特定的细胞类型(例如，血液、皮肤等)表达特定的蛋白质基因子集，并使其余基因沉默。为了阐明导致基因被激活或关闭的机制，我们研究了被称为“CpG岛”(CGI)的DNA序列。这些序列存在于超过一半的人类基因中，根据DNA上甲基的存在或不存在而处于活跃或沉默状态。我们设计了一种纯化所有CGI的方法，结果显示，出人意料的是，只有一半发生在启动子附近的基因开始处，其余的发生在基因内部或基因之间。值得注意的是，CGI的甲基化导致稳定的基因沉默。我们在四个人体组织中测试了17,000个CGI，发现每个组织中都有6%-8%的CGI甲基化。蛋白质产物在胚胎发育过程中起关键作用的基因优先甲基化，这表明发育过程中的基因表达可能受到CGI甲基化的调节。CpG岛甲基化是一种表观遗传现象，通常与疾病中的异常有关，在“正常”人类细胞的背景下很少被描述。在这里，我们强调组织特异性的CpG岛甲基化，它经常与发育基因相关。
CpG islands (CGIs) are dense clusters of CpG sequences that punctuate the CpG-deficient human genome and associate with many gene promoters. As CGIs also differ from bulk chromosomal DNA by their frequent lack of cytosine methylation, we devised a CGI enrichment method based on nonmethylated CpG affinity chromatography. The resulting library was sequenced to define a novel human blood CGI set that includes many that are not detected by current algorithms. Approximately half of CGIs were associated with annotated gene transcription start sites, the remainder being intra- or intergenic. Using an array representing over 17,000 CGIs, we established that 6%–8% of CGIs are methylated in genomic DNA of human blood, brain, muscle, and spleen. Inter- and intragenic CGIs are preferentially susceptible to methylation. CGIs showing tissue-specific methylation were overrepresented at numerous genetic loci that are essential for development, including HOX and PAX family members. The findings enable a comprehensive analysis of the roles played by CGI methylation in normal and diseased human tissues. The human genome contains about 22,000 genes, each encoding one of the proteins required for human life. A particular cell type (e.g., blood, skin, etc.) expresses a specific subset of protein genes and silences the remainder. To shed light on the mechanisms that cause genes to be activated or shut down, we studied DNA sequences called “CpG islands” (CGIs). These sequences are found at over half of all human genes and can exist in either the active or silent state depending on the presence or absence of methyl groups on the DNA. We devised a method for purifying all CGIs and showed that, unexpectedly, only half occur at the beginning of genes near the promoter, the rest occurring within or between genes. Notably, methylation of CGIs causes stable gene silencing. We tested 17,000 CGIs in four human tissues and found that 6%–8% were methylated in each. Genes whose protein products play an essential role during embryonic development were preferentially methylated, suggesting that gene expression during development could be regulated by CGI methylation. CpG island methylation, an epigenetic phenomenon usually associated with abnormality in disease, is little characterised in the context of "normal" human cells. Here we highlight tissue-specific CpG Island methylation, which frequently associates with developmental genes.
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