Figure 1.

Paternal allele CTCF binding is blocked by methylation of the IGF2/H19 ICR, allowing distal enhancers to act on the IGF2 promoter resulting in normal gene dosage. Lack of methylation of the maternal ICR allows CTCF to bind to the maternal ICR creating a physical barrier blocking the distal enhancers and preventing their access to the IGF2 promoter region. CTCF also binds to the promotor region of IGF2 and subsequently forms a dimer via chromosomal looping with the ICR bound CTCF protein. This dimer recruits PRC2 via binding to the zinc finger subunit SUZ12. Another member of PRC2, EZH2, initiates H3K27 methylation and shuts down the IGF2 promoter. Mutations in the gene region of the ICR are known to cause BWS via abrogation of CTCF binding. Abbreviations: CTCF= CCCTC-binding factor; EZH2 = enhancer of zeste homolog 2; PRC2 = polycomb repressive Complex 2; IGF2 = Insulin-like growth factor 2; ICR=imprinting control region DMR=differentially methylated region