The nucleotides responsible for the direct physical contact between the chromatin insulator protein CTCF and theH19imprinting control region manifest parent of origin-specific long-distance insulation and methylation-free domains

Abstract

The repression of the maternally inheritedIgf2allele has been proposed to depend on a methylation-sensitive chromatin insulator organized by the 11 zinc finger protein CTCF at theH19imprinting control region (ICR). Here we document that point mutations of the nucleotides in physical contact with CTCF within the endogenousH19ICR lead to loss of CTCF binding andIgf2imprinting only when passaged through the female germline. This effect is accompanied by a significant loss of methylation protection of the maternally derivedH19ICR. Because CTCF interacts with other imprinting control regions, it emerges as a central factor responsible for interpreting and propagating gamete-derived epigenetic marks and for organizing epigenetically controlled expression domains.