1Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, Università degli Studi della Campania "Luigi Vanvitelli", Caserta, Italy.
2Istituto di Genetica e Biofisica "Adriano Buzzati-Traverso", Consiglio Nazionale delle Ricerche CNR, Naples, Italy.
Clin Epigenetics. 2018 Feb 21;10:23. doi: 10.1186/s13148-018-0454-7. eCollection 2018.
Loss of paternal methylation (LOM) of the intergenic differentially methylated region (:IG-DMR) causes alteration of imprinting and Silver-Russell syndrome (SRS). Recently, internal deletions of the :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.
The presence of several target sites (ZTSs) and three demonstrated binding regions (BRs) for the imprinting factor ZFP57 in the :IG-DMR suggest the involvement of this factor in the maintenance of methylation of this locus. By comparing the extension of the :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.
The generation of transgenic mouse lines in which the endogenous :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.
Similarly to what is proposed for maternally inherited BWS mutations and CTCF and OCT4/SOX2 binding, we suggest that deletions of the :IG-DMR result in SRS with LOM if ZFP57 binding on the paternal chromosome is affected.
基因间差异甲基化区域（IG-DMR）的父源甲基化丢失（LOM）会导致印迹异常和 Silver-Russell 综合征（SRS）。最近，当 IG-DMR 内部缺失存在于父染色体上时，与 LOM 和 SRS 相关。相比之下，以前描述的缺失，其中大多数在母系遗传时会导致甲基化增加（GOM）和 Beckwith-Wiedemann 综合征（BWS），如果父系遗传，则始终与正常甲基化和表型相关。
IG-DMR 中存在几个靶位点（ZTSs）和三个已证明的印迹因子 ZFP57 结合区域（BRs），表明该因子参与维持该基因座的甲基化。通过比较 IG-DMR 缺失的延伸与 ZFP57 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 ZFP57 结合的干扰。事实上，强烈影响 ZFP57 BR 的缺失会导致 LOM 和 SRS，而在每个 BR 中保留大量 ZFPs 的缺失不会改变甲基化，并且与正常表型相关。
通过生成内源 IG-DMR 被包括三个 ZFP57 BR 或其突变版本的人同源基因座取代的转基因小鼠系，将允许测试 ZFP57 结合在印迹甲基化和生长表型中的作用。
与母体遗传的 BWS 突变和 CTCF 以及 OCT4/SOX2 结合所提出的类似，我们建议如果父系染色体上的 ZFP57 结合受到影响，IG-DMR 的缺失会导致 SRS 伴 LOM。
