Cell type-specific DNA methylation at intragenic CpG islands in the immune system
Cell type-specific DNA methylation at intragenic CpG islands in the immune system
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DOI：
10.1101/gr.118703.110
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发表时间：
2011-07-01
期刊：
影响因子：
7
通讯作者：
Bird, Adrian
中科院分区：
文献类型：
--
作者：
Deaton, Aimee M.;Webb, Shaun;Bird, Adrian
人类和小鼠基因组包含相似数量的 CpG 岛 (CGI)，它们是与转录起始位点相关的离散的富含 CpG 的 DNA 序列。在这两个物种中，大约 50% 的 CGI 远离注释的启动子，但通常具有类似启动子的特征。为了确定 CGI 甲基化在细胞分化中的作用，我们分析了小鼠造血谱系细胞中综合 CGI 组的 DNA 甲基化。使用一种可能检测到大约 33% 处于甲基化状态的基因组 CpG 的方法，我们发现基因表达的巨大差异伴随着令人惊讶的少量 DNA 甲基化变化。然而，造血细胞和远亲组织大脑之间存在许多 DNA 甲基化差异。免疫系统中 DNA 甲基化的改变主要发生在基因体内的 CGI，其具有细胞类型限制启动子的特性，但很少发生在注释基因启动子或 CGI 侧翼序列（CGI“shores”）。出乎意料的是，基因内 CGI 甲基化升高与相关基因的沉默相关。差异甲基化的基因内 CGI 往往缺乏 H3K4me3，并与转录抑制环境相关。无论甲基化状态如何，我们的结果表明 DNA 甲基化变化在分化的后期发挥相对较小的作用，并表明基因内 CGI 代表谱系规范早期阶段差异基因表达的调节位点。
Human and mouse genomes contain a similar number of CpG islands (CGIs), which are discrete CpG-rich DNA sequences associated with transcription start sites. In both species, similar to 50% of all CGIs are remote from annotated promoters but, nevertheless, often have promoter-like features. To determine the role of CGI methylation in cell differentiation, we analyzed DNA methylation at a comprehensive CGI set in cells of the mouse hematopoietic lineage. Using a method that potentially detects similar to 33% of genomic CpGs in the methylated state, we found that large differences in gene expression were accompanied by surprisingly few DNA methylation changes. There were, however, many DNA methylation differences between hematopoietic cells and a distantly related tissue, brain. Altered DNA methylation in the immune system occurred predominantly at CGIs within gene bodies, which have the properties of cell type-restricted promoters, but infrequently at annotated gene promoters or CGI flanking sequences (CGI "shores''). Un-expectedly, elevated intragenic CGI methylation correlated with silencing of the associated gene. Differentially methylated intragenic CGIs tended to lack H3K4me3 and associate with a transcriptionally repressive environment regardless of methylation state. Our results indicate that DNA methylation changes play a relatively minor role in the late stages of differentiation and suggest that intragenic CGIs represent regulatory sites of differential gene expression during the early stages of lineage specification.