Is ZFP57 binding to H19/IGF2: IG-DMR affected in Silver-Russell syndrome?
Is ZFP57 binding to H19/IGF2: IG-DMR affected in Silver-Russell syndrome?
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DOI：
10.1186/s13148-018-0454-7
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发表时间：
2018-02-21
影响因子：
5.7
通讯作者：
Riccio, Andrea
中科院分区：
文献类型：
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作者：
Sparago, Angela;Cerrato, Flavia;Riccio, Andrea
背景资料：H19/IGF 2基因间差异甲基化区域（H19/IGF 2：IG-DMR）的父系甲基化（LOM）缺失导致H19/IGF 2印迹改变和Silver-Russell综合征（SRS）。最近，H19/IGF 2：IG-DMR的内部缺失与存在于父系染色体上的LOM和SRS相关。相反，先前描述的缺失，其中大部分导致甲基化增益（GOM）和Beckwith-Wiedemann综合征（BWS）的母体传播，始终与正常的甲基化和表型，如果父系遗传。IG-DMR表明该因子参与该基因座甲基化的维持。通过比较H19/IGF 2：IG-DMR缺失的延伸与ZFP 57的结合谱，我们提出缺失对DNA甲基化和临床表型的影响取决于它们对ZFP 57结合的干扰。实际上，强烈影响ZFP 57 BR的缺失导致LOM和SRS，而在每个BR中保留大量ZFP的缺失不改变甲基化并且与正常表型相关。IG-DMR被包括三个ZFP 57 BR的人正向同源基因座取代或其突变形式将允许测试ZFP 57结合在印迹甲基化和生长中的作用该假设的含义：类似于针对母系遗传的BWS突变和CTCF和OCT 4/SOX 2结合提出的内容，我们认为如果ZFP 57在父系染色体上的结合受到影响，则H19/IGF 2：IG-DMR的缺失导致SRS伴LOM。
Background: Loss of paternal methylation (LOM) of the H19/IGF2 intergenic differentially methylated region (H19/IGF2: IG-DMR) causes alteration of H19/IGF2 imprinting and Silver-Russell syndrome (SRS). Recently, internal deletions of the H19/IGF2: IG-DMR have been associated with LOM and SRS when present on the paternal chromosome. In contrast, previously described deletions, most of which cause gain of methylation (GOM) and Beckwith-Wiedemann syndrome (BWS) on maternal transmission, were consistently associated with normal methylation and phenotype if paternally inherited.Presentation of the hypothesis: The presence of several target sites (ZTSs) and three demonstrated binding regions (BRs) for the imprinting factor ZFP57 in the H19/IGF2: IG-DMR suggest the involvement of this factor in the maintenance of methylation of this locus. By comparing the extension of the H19/IGF2: IG-DMR deletions with the binding profile of ZFP57, we propose that the effect of the deletions on DNA methylation and clinical phenotype is dependent on their interference with ZFP57 binding. Indeed, deletions strongly affecting a ZFP57 BR result in LOM and SRS, while deletions preserving a significant number of ZFPs in each BR do not alter methylation and are associated with normal phenotype.Testing the hypothesis: The generation of transgenic mouse lines in which the endogenous H19/IGF2: IG-DMR is replaced by the human orthologous locus including the three ZFP57 BRs or their mutant versions will allow to test the role of ZFP57 binding in imprinted methylation and growth phenotype.Implications of the hypothesis: Similarly to what is proposed for maternally inherited BWS mutations and CTCF and OCT4/SOX2 binding, we suggest that deletions of the H19/IGF2: IG-DMR result in SRS with LOM if ZFP57 binding on the paternal chromosome is affected.