Hyper- and hypomethylation at the IGF2-H19 imprinting control region (ICR) 
result in reciprocal changes in IGF2-H19 expression and the two contrasting 
growth disorders, Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome 
(SRS). DNA methylation of the ICR controls the reciprocal imprinting of IGF2 and 
H19 by preventing the binding of the insulator protein, CTCF. We here show that 
local changes in histone modifications and CTCF--cohesin binding at the ICR in 
BWS and SRS together with DNA methylation correlate with the higher order 
chromatin structure at the locus. In lymphoblastoid cells from control 
individuals, we found the repressive histone H3K9me3 and H4K20me3 marks 
associated with the methylated paternal ICR allele and the bivalent 
H3K4me2/H3K27me3 mark together with H3K9ac and CTCF--cohesin associated with the 
non-methylated maternal allele. In patient-derived cell lines, the mat/pat 
asymmetric distribution of these epigenetic marks was lost with H3K9me3 and 
H4K20me3 becoming biallelic in the BWS and H3K4me2, H3K27me3 and H3K9ac together 
with CTCF-cohesin becoming biallelic in the SRS. We further show that in BWS and 
SRS cells, there is opposing chromatin looping conformation mediated by 
CTCF--cohesin binding sites surrounding the locus. In normal cells, lack of 
CTCF--cohesin binding at the paternal ICR is associated with monoallelic 
interaction between two CTCF sites flanking the locus. CTCF--cohesin binding at 
the maternal ICR blocks this interaction by associating with the CTCF site 
downstream of the enhancers. The two alternative chromatin conformations are 
differently favoured in BWS and SRS likely predisposing the locus to the 
activation of IGF2 or H19, respectively.