Fundamental diversity of human CpG islands at multiple biological levels.
Fundamental diversity of human CpG islands at multiple biological levels.
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作者：
Zeng J;Nagrajan HK;Yi SV
CpG岛(CGI)通常被用作基因组标记来研究DNA甲基化的模式和调控后果。有趣的是，最近的研究揭示了CGI之间的显著差异：例如，长CGI和短CGI在基因表达复杂性和核小体占有率方面表现出相反的模式。CGI的进化起源也具有高度的异质性。为了系统地评估CGI之间的潜在多样性，并最终阐明CGI的多样性与其表观遗传变异之间的联系，我们分析了多个细胞来源的核苷酸分辨DNA甲基化图谱。我们根据DNA甲基化的模式发现了新的CGI簇：稳定的低甲基化CGI簇(簇I)、精子低甲基化的CGI簇(簇II)和可变甲基化的CGI簇(簇III)。这些表观基因组CGI簇在包括基因组、进化和功能特征在内的多种生物学特征上具有显著的差异。在基因组水平上，稳定的低甲基化CGI簇往往比其他簇更长，含有更多的CpG二核苷酸。它们也经常与启动子相关，而CGI簇II和III大多位于基因内或基因间区域，并表现出高度组织特异性的DNA甲基化。功能本体术语和转录配置文件与CGI簇一起变化，表明CGI的调节功能与它们的异质性密切相关。最后，与疾病、衰老和印记等独特生物过程相关的CGI在CGI集群中不成比例地发生。这些新的发现提供了一种有效的手段，将现有的关于CGI的知识结合到基因组背景中，同时带来新的见解，阐明DNA甲基化在不同生物条件和人口统计学中的意义。
CpG islands (CGIs) are commonly used as genomic markers to study the patterns and regulatory consequences of DNA methylation. Interestingly, recent studies reveal a substantial diversity among CGIs: long and short CGIs, for example, exhibit contrasting patterns of gene expression complexity and nucleosome occupancy. Evolutionary origins of CGIs are also highly heterogeneous. In order to systematically evaluate potential diversities among CGIs and ultimately to illuminate the link between diversity of CGIs and their epigenetic variation, we analyzed the nucleotide-resolution DNA methylation maps (methylomes) of multiple cellular origins. We discover novel ‘clusters’ of CGIs according to their patterns of DNA methylation; the stably hypomethylated CGI cluster (cluster I), sperm-hypomethylated CGI cluster (cluster II), and variably methylated CGI cluster (cluster III). These epigenomic CGI clusters are strikingly distinct at multiple biological features including genomic, evolutionary, and functional characteristics. At the genomic level, the stably hypomethylated CGI cluster tends to be longer and harbors many more CpG dinucleotides than those in other clusters. They are also frequently associated with promoters, while CGI clusters II and III mostly reside in intragenic or intergenic regions and exhibit highly tissue-specific DNA methylation. Functional ontology terms and transcriptional profiles co-vary with CGI clusters, indicating that the regulatory functions of CGIs are tightly linked to their heterogeneity. Finally, CGIs associated with distinctive biological processes, such as diseases, aging, and imprinting, occur disproportionately across CGI clusters. These new findings provide an effective means to combine existing knowledge on CGIs into a genomic context while bringing new insights that elucidate the significance of DNA methylation across different biological conditions and demography.