EPIGENETICS AND GENOMIC IMPRINTING

Epigenetics and Genomic Imprinting: Role of H19 and IGF2 genes in the pathogenesis of Russell - Silver Syndrome

Epigenetics and Genomic Imprinting : Role of H19 and IGF2 genes in the pathogenesis of Russell - Silver Syndrome

Nearly a decade ago, in an extensive review, Arney compiled numerous genetic experiments carried out on theIgf2/H19 ICR1 domain and emphasised the complexity of the region and contradictions between some of the models, especially when it came to expression data. The addition of new mouse models which disrupt the Igf2/H19 ICR1 domain as well as the identification of new trans-regulatory factors and new genetic defects in BWS and SRS make things even more complex in 2012 (Leach & Chudoba, 2007).

The mouse ICR1 deletion/mutation models developed between 2003 and 2011 have been initially designed to investigate the exact role of CTCF in protecting the ICR1 maternal allele from DNA methylation. Meanwhile, other trans-acting factors have been identified and increasing data have shown that CTCF function is modulated by neighbouring DNA binding factors. It is important to discuss the role of those other factors in order to analyse accurately the various mouse models.

There are some ZFP57 motifs within ICR1 in both mice (six motifs) and humans (nine motifs), some of them immunoprecipitated in CHIP experiments. Moreover, an interesting aspect of these ZFP57 hexanucleotide (TGCCGC) binding motifs is that they overlap three of the four CTCF binding sites of the mouse ICR1 domain and the seven CTCF binding sites of the human ICR1 domain.

The IGF2/H19 imprinting control region (ICR)1 domain. (A) Mouse ICR1 (H19 DMD) with location of the various transcription factor binding sites and various deletions within ICR1. (B) Human ICR1 with location of the various transcription factor binding sites. ICR1 is organised into two clusters each containing one 450 bp A-repeat followed by three to four 400 bp B-repeats (Kotzot & Schmitt, 1995). A plausible explanation to the opposite phenotypes upon different parental transmission is that CTCF binding sites are lost on maternal transmission, whereas the ZFP57 binding sites are lost on paternal transmission.

Various studies also mutated three to four of the CTCF binding sites of the mouse ICR1Most mutations abrogated CTCF binding resulting in loss of the insulator function and overgrowth upon maternal transmission. They did not result in any phenotype upon paternal transmission although the ZFP57 motifs were deleted in at least two of the models. The fifth model gives the opposite phenotype with a gain of insulator function upon paternal transmission and fetal growth retardation. In this model, the mutations (mutations of nine of the 10 CpG dinucleotides present in the four CTCF binding sites) were less severe and did not affect the binding of CTCF (Kotzot & Schmitt, 1995).

Other factors possibly involved in the regulation of ICR1 imprinting are pluripotency factors. We and others recently identified mutations/small deletions of OCT4 and SOX2 binding sites within ICR1 in BWS patients with ICR1 gain of methylation (figure 3B). In the four cases described so far, the BWS phenotype segregated with transmission of the mutation through the female germline with no phenotype ...