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非随机的、个体特异性的甲基化图谱存在于人类H19/IGF2印记控制区域的第六个CTCF结合位点。

Non-random, individual-specific methylation profiles are present at the sixth CTCF binding site in the human H19/IGF2 imprinting control region.

作者信息

Tost Jörg, Jammes Hélène, Dupont Jean-Michel, Buffat Christophe, Robert Brigitte, Mignot Thérèse-Marie, Mondon Françoise, Carbonne Bruno, Siméoni Umberto, Grangé Gilles, Kerjean Antoine, Ferré Françoise, Gut Ivo Glynne, Vaiman Daniel

机构信息

Laboratoire d'Epigénétique, Centre National de Génotypage, 2 rue Gaston Crémieux, 91000 Evry, France.

出版信息

Nucleic Acids Res. 2006;34(19):5438-48. doi: 10.1093/nar/gkl657. Epub 2006 Sep 29.

DOI:10.1093/nar/gkl657
PMID:17012269
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1636469/
Abstract

Expression of imprinted genes is classically associated with differential methylation of specific CpG-rich DNA regions (DMRs). The H19/IGF2 locus is considered a paradigm for epigenetic regulation. In mice, as in humans, the essential H19 DMR--target of the CTCF insulator--is located between the two genes. Here, we performed a pyrosequencing-based quantitative analysis of its CpG methylation in normal human tissues. The quantitative analysis of the methylation level in the H19 DMR revealed three unexpected discrete, individual-specific methylation states. This epigenetic polymorphism was confined to the sixth CTCF binding site while a unique median-methylated profile was found at the third CTCF binding site as well as in the H19 promoter. Monoallelic expression of H19 and IGF2 was maintained independently of the methylation status at the sixth CTCF binding site and the IGF2 DMR2 displayed a median-methylated profile in all individuals and tissues analyzed. Interestingly, the methylation profile was genetically transmitted. Transgenerational inheritance of the H19 methylation profile was compatible with a simple model involving one gene with three alleles. The existence of three individual-specific epigenotypes in the H19 DMR in a non-pathological situation means it is important to reconsider the diagnostic value and functional importance of the sixth CTCF binding site.

摘要

印记基因的表达通常与特定富含CpG的DNA区域（差异甲基化区域，DMRs）的甲基化差异相关。H19/IGF2基因座被认为是表观遗传调控的范例。在小鼠中，如同在人类中一样，关键的H19 DMR（CTCF绝缘子的靶标）位于这两个基因之间。在此，我们对正常人体组织中其CpG甲基化进行了基于焦磷酸测序的定量分析。对H19 DMR甲基化水平的定量分析揭示了三种意外的离散、个体特异性甲基化状态。这种表观遗传多态性局限于第六个CTCF结合位点，而在第三个CTCF结合位点以及H19启动子中发现了独特的中等甲基化谱。H19和IGF2的单等位基因表达独立于第六个CTCF结合位点的甲基化状态得以维持，并且IGF2 DMR2在所有分析的个体和组织中均显示出中等甲基化谱。有趣的是，甲基化谱是可遗传传递的。H19甲基化谱的跨代遗传与一个涉及具有三个等位基因的单一基因的简单模型相符。在非病理情况下H19 DMR中存在三种个体特异性表观基因型意味着有必要重新考虑第六个CTCF结合位点的诊断价值和功能重要性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/1636469/fb68da114c64/gkl657f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/1636469/91f8a49d37f5/gkl657f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/1636469/ddc4b8b57834/gkl657f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/1636469/15ab3fa86023/gkl657f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/1636469/6b22cd53a09b/gkl657f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/1636469/843ced09b8d7/gkl657f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/1636469/303f7b3c3d2a/gkl657f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/1636469/fb68da114c64/gkl657f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/1636469/91f8a49d37f5/gkl657f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/1636469/ddc4b8b57834/gkl657f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/1636469/15ab3fa86023/gkl657f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/1636469/6b22cd53a09b/gkl657f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/1636469/843ced09b8d7/gkl657f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/1636469/303f7b3c3d2a/gkl657f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/1636469/fb68da114c64/gkl657f7.jpg

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本文引用的文献

1
CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2.CTCF在H19印记控制区域的结合介导了母系遗传的高阶染色质构象，以限制增强子对Igf2的作用。
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Serial pyrosequencing for quantitative DNA methylation analysis.用于定量DNA甲基化分析的焦磷酸测序技术
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