Disruption of genomic neighbourhood at the imprinted IGF2-H19 locus in Beckwith-Wiedemann syndrome and Silver-Russell syndrome.
Disruption of genomic neighbourhood at the imprinted IGF2-H19 locus in Beckwith-Wiedemann syndrome and Silver-Russell syndrome.
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DOI：
10.1093/hmg/ddr018
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发表时间：
2011-04-01
影响因子：
3.5
通讯作者：
Murrell A
中科院分区：
文献类型：
--
作者：
Nativio R;Sparago A;Ito Y;Weksberg R;Riccio A;Murrell A
IGF2-H19印迹控制区(ICR)的高甲基化和低甲基化导致IGF2-H19表达的相互变化和两种截然不同的生长障碍，Beckwith-Wiedemann综合征(BWS)和Silver-Russell综合征(SRS)。ICR的DNA甲基化通过阻止绝缘蛋白CTCF的结合来控制IGF2和H19的相互印迹。我们在这里表明，在BWS和SRS中，组蛋白修饰和ICR上CTCF-粘附素结合的局部变化以及DNA甲基化与该基因座的高阶染色质结构相关。在对照组的淋巴母细胞中，我们发现了与父亲的ICR等位基因相关的抑制性组蛋白H3K9me3和H4K20me3标记，以及与未甲基化的母亲等位基因相关的二价H3K4me2/H3K27me3标记以及H3K9ac和CTCF粘附素。在患者来源的细胞系中，这些表观遗传标记的MAT/PAT不对称分布丢失，H3K9me3和H4K20me3在BWS中成为双等位基因，H3K4me2、H3K27me3和H3K9ac与CTCF-粘附素一起在SRS中成为双等位基因。我们进一步证明，在BWS和SRS细胞中，存在由CTCF-粘附素结合位点介导的相反的染色质环状构象。在正常细胞中，在父本ICR缺乏CTCF-粘附素结合与该基因两侧两个CTCF位点之间的单等位基因相互作用有关。母体ICR上的CTCF-粘附素结合通过与增强子下游的CTCF位点结合来阻止这种相互作用。这两种可供选择的染色质构象在BWS和SRS中有不同的偏好，可能分别使该基因座易于激活IGF2或H19。
Hyper- and hypomethylation at the IGF2-H19 imprinting control region (ICR) result in reciprocal changes in IGF2-H19 expression and the two contrasting growth disorders, Beckwith–Wiedemann syndrome (BWS) and Silver–Russell syndrome (SRS). DNA methylation of the ICR controls the reciprocal imprinting of IGF2 and H19 by preventing the binding of the insulator protein, CTCF. We here show that local changes in histone modifications and CTCF–cohesin binding at the ICR in BWS and SRS together with DNA methylation correlate with the higher order chromatin structure at the locus. In lymphoblastoid cells from control individuals, we found the repressive histone H3K9me3 and H4K20me3 marks associated with the methylated paternal ICR allele and the bivalent H3K4me2/H3K27me3 mark together with H3K9ac and CTCF–cohesin associated with the non-methylated maternal allele. In patient-derived cell lines, the mat/pat asymmetric distribution of these epigenetic marks was lost with H3K9me3 and H4K20me3 becoming biallelic in the BWS and H3K4me2, H3K27me3 and H3K9ac together with CTCF–cohesin becoming biallelic in the SRS. We further show that in BWS and SRS cells, there is opposing chromatin looping conformation mediated by CTCF–cohesin binding sites surrounding the locus. In normal cells, lack of CTCF–cohesin binding at the paternal ICR is associated with monoallelic interaction between two CTCF sites flanking the locus. CTCF–cohesin binding at the maternal ICR blocks this interaction by associating with the CTCF site downstream of the enhancers. The two alternative chromatin conformations are differently favoured in BWS and SRS likely predisposing the locus to the activation of IGF2 or H19, respectively.
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