CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2
CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2
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DOI：
10.1073/pnas.0600326103
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发表时间：
2006-07-11
影响因子：
11.1
通讯作者：
Ohlsson, Rolf
中科院分区：
文献类型：
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作者：
Kurukuti, Sreenivasulu;Tiwari, Vijay Kumar;Ohlsson, Rolf
据认为，H19印迹控制区（ICR）通过CTCF依赖性染色质绝缘子指导母系遗传的Igf2等位基因的沉默。ICR已被证明与Igf2中的沉默区（差异甲基化区（DMR）1）物理相互作用，但CTCF在该染色质环中的作用以及它是否限制远端增强子对Igf2的物理访问尚不清楚。我们在Igf2/H19区域超过160 kb的区域进行了系统的染色体构象捕获分析，鉴定了与远端增强子和ICR物理相互作用的序列。我们发现，在父亲染色体上，增强子与Igf 2启动子相互作用，但在母亲等位基因上，这被H19 ICR内的CTCF结合阻止。CTCF在母体ICR中的结合调节其与Igf2处的基质附着区（MAR）3和DMR 1的相互作用，从而在母体Igf2基因座周围形成紧密环，这可能有助于其沉默。H19 ICR中CTCF结合位点的突变导致CTCF结合的丧失和Igf2 DMR 1内CTCF靶位点的从头甲基化，表明CTCF可以协调区域表观遗传标记。这种系统的染色体构象捕获分析的印迹集群揭示，CTCF具有重要的作用，在表观遗传调控的高阶染色质结构和基因沉默在相当长的距离在基因组中。
It is thought that the H19 imprinting control region (ICR) directs the silencing of the maternally inherited Igf2 allele through a CTCF-dependent chromatin insulator. The ICR has been shown to interact physically with a silencer region in Igf2, differentially methylated region (DMR)1, but the role of CTCF in this chromatin loop and whether it restricts the physical access of distal enhancers to Igf2 is not known. We performed systematic chromosome conformation capture analyses in the Igf2/H19 region over > 160 kb, identifying sequences that interact physically with the distal enhancers and the ICR. We found that, on the paternal chromosome, enhancers interact with the Igf2 promoters but that, on the maternal allele, this is prevented by CTCF binding within the H19 ICR. CTCF binding in the maternal ICR regulates its interaction with matrix attachment region (MAR)3 and DMR1 at Igf2, thus forming a tight loop around the maternal Igf2 locus, which may contribute to its silencing. Mutation of CTCF binding sites in the H19 ICR leads to loss of CTCF binding and de novo methylation of a CTCF target site within Igf2 DMR1, showing that CTCF can coordinate regional epigenetic marks. This systematic chromosome conformation capture analysis of an imprinting cluster reveals that CTCF has a critical role in the epigenetic regulation of higher-order chromatin structure and gene silencing over considerable distances in the genome.