Is ZFP57 binding to :IG-DMR affected in Silver-Russell syndrome?

Background: 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.

Presentation Of The Hypothesis: 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.

Testing The Hypothesis: 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.

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 :IG-DMR result in SRS with LOM if ZFP57 binding on the paternal chromosome is affected.