Loss of CpG methylation is strongly correlated with loss of histone H3 lysine 9 methylation at DMR-LIT1 in patients with Beckwith-Wiedemann syndrome
Loss of CpG methylation is strongly correlated with loss of histone H3 lysine 9 methylation at DMR-LIT1 in patients with Beckwith-Wiedemann syndrome
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DOI：
10.1086/378595
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发表时间：
2003-10-01
影响因子：
9.8
通讯作者：
Soejima, H
中科院分区：
文献类型：
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作者：
Higashimoto, K;Urano, T;Soejima, H
为了阐明11p15.5染色体上p57(KIP2)/LIT1亚结构域的染色质印迹机制和7F5染色体上的小鼠同源物，我们研究了LIT1 /LIT1差异CpG甲基化区域（DMR-Lit1/LIT1）的组蛋白修饰状态，该区域是该亚结构域的印迹控制区域，在一半的Beckwith-Wiedemann综合征（BWS）患者中发生去甲基化。染色质免疫沉淀实验显示，在这两个物种中，具有cpg甲基化的母系无活性等位基因的DMR-Lit1/LIT1显示组蛋白H3 Lys9甲基化，而cpg未甲基化的父系活性等位基因在组蛋白H3/H4上乙酰化，在H3 Lys4上甲基化。我们还研究了BWS患者CpG甲基化与DMR-LIT1组蛋白H3 Lys9甲基化之间的关系。在正常个体和DMR-LIT1甲基化正常的BWS患者中，在母体等位基因上检测到组蛋白H3 Lys9甲基化；而DMR-LIT1印迹缺损患者则完全消失。这些发现表明，DMR-Lit1/LIT1的组蛋白修饰状态在亚域内的印迹控制中起着重要作用，组蛋白H3 Lys9甲基化的缺失以及母体等位基因上CpG的去甲基化可能导致BWS表型。
To clarify the chromatin-based imprinting mechanism of the p57(KIP2)/LIT1 subdomain at chromosome 11p15.5 and the mouse ortholog at chromosome 7F5, we investigated the histone-modification status at a differentially CpG methylated region of Lit1/LIT1 (DMR-Lit1/LIT1), which is an imprinting control region for the subdomain and is demethylated in half of patients with Beckwith-Wiedemann syndrome (BWS). Chromatin-immunoprecipitation assays revealed that, in both species, DMR-Lit1/LIT1 with the CpG-methylated, maternally derived inactive allele showed histone H3 Lys9 methylation, whereas the CpG-unmethylated, paternally active allele was acetylated on histone H3/H4 and methylated on H3 Lys4. We have also investigated the relationship between CpG methylation and histone H3 Lys9 methylation at DMR-LIT1 in patients with BWS. In a normal individual and in patients with BWS with normal DMR-LIT1 methylation, histone H3 Lys9 methylation was detected on the maternal allele; however, it disappeared completely in the patients with the DMR-LIT1 imprinting defect. These findings suggest that the histone-modification status at DMR-Lit1/LIT1 plays an important role in imprinting control within the subdomain and that loss of histone H3 Lys9 methylation, together with CpG demethylation on the maternal allele, may lead to the BWS phenotype.