The molecular function and clinical phenotype of partial deletions of the IGF2/H19 imprinting control region depends on the spatial arrangement of the remaining CTCF-binding sites.
The molecular function and clinical phenotype of partial deletions of the IGF2/H19 imprinting control region depends on the spatial arrangement of the remaining CTCF-binding sites.
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DOI：
10.1093/hmg/dds465
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发表时间：
2013-02-01
影响因子：
3.5
通讯作者：
Riccio A
中科院分区：
文献类型：
--
作者：
Beygo J;Citro V;Sparago A;De Crescenzo A;Cerrato F;Heitmann M;Rademacher K;Guala A;Enklaar T;Anichini C;Cirillo Silengo M;Graf N;Prawitt D;Cubellis MV;Horsthemke B;Buiting K;Riccio A
在染色体11p15.5处，印记中心1（IC 1）控制IGF 2和H19基因的来源特异性表达的亲本。5 kb IC 1区域包含锌指蛋白CTCF的多个靶位点（CTS），其在母体染色体上的结合阻止IGF 2的激活，并允许H19通过常见的增强子激活。CTCF结合有助于保持母体IC 1甲基化，而在父亲染色体上配子遗传的DNA甲基化抑制CTCF相互作用和增强子阻断活性，导致IGF 2激活和H19沉默。母系遗传的1.4-2.2 kb缺失与残留CTS的甲基化和Beckwith-Wiedemann综合征相关，尽管具有不同的表达率和表达度。我们探讨了IC 1微缺失和表型之间的关系，通过分析一些以前描述的和新的突变等位基因。我们使用了基于下一代测序的高度定量分析来测量受影响家族的DNA甲基化，并分析了培养细胞中的增强子阻断活性和CTCF结合。我们证明，微缺失主要影响IC 1功能和CTCF结合通过改变CTS间距。因此，IC 1失活的程度和临床表型受到残留CTS排列的影响。与野生型等位基因相似的CTS间隔导致中度IC 1失活，并与母体IC 1的随机DNA甲基化和不完全DNA甲基化相关。具有不同CTS间距的微缺失显示严重的IC 1失活，并且与IC 1高甲基化和完全失活相关。因此，需要对IC 1微缺失进行仔细表征，以预测复发风险和表型结局。
At chromosome 11p15.5, the imprinting centre 1 (IC1) controls the parent of origin-specific expression of the IGF2 and H19 genes. The 5 kb IC1 region contains multiple target sites (CTS) for the zinc-finger protein CTCF, whose binding on the maternal chromosome prevents the activation of IGF2 and allows that of H19 by common enhancers. CTCF binding helps maintaining the maternal IC1 methylation-free, whereas on the paternal chromosome gamete-inherited DNA methylation inhibits CTCF interaction and enhancer-blocking activity resulting in IGF2 activation and H19 silencing. Maternally inherited 1.4–2.2 kb deletions are associated with methylation of the residual CTSs and Beckwith–Wiedemann syndrome, although with different penetrance and expressivity. We explored the relationship between IC1 microdeletions and phenotype by analysing a number of previously described and novel mutant alleles. We used a highly quantitative assay based on next generation sequencing to measure DNA methylation in affected families and analysed enhancer-blocking activity and CTCF binding in cultured cells. We demonstrate that the microdeletions mostly affect IC1 function and CTCF binding by changing CTS spacing. Thus, the extent of IC1 inactivation and the clinical phenotype are influenced by the arrangement of the residual CTSs. A CTS spacing similar to the wild-type allele results in moderate IC1 inactivation and is associated with stochastic DNA methylation of the maternal IC1 and incomplete penetrance. Microdeletions with different CTS spacing display severe IC1 inactivation and are associated with IC1 hypermethylation and complete penetrance. Careful characterization of the IC1 microdeletions is therefore needed to predict recurrence risks and phenotypical outcomes.
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影响因子：
1.9
作者：
De Crescenzo A;Coppola F;Falco P;Bernardo I;Ausanio G;Cerrato F;Falco L;Riccio A
通讯作者：
Riccio A
影响因子：
5.3
作者：
Pant, V;Kurukuti, S;Ohlsson, R
通讯作者：
Ohlsson, R
影响因子：
30.8
作者：
Sparago, A;Cerrato, F;Riccio, A
通讯作者：
Riccio, A
影响因子：
3.5
作者：
Cerrato, F;Sparago, A;Riccio, A
通讯作者：
Riccio, A
影响因子：
64.8
作者：
Hark, AT;Schoenherr, CJ;Tilghman, SM
通讯作者：
Tilghman, SM