The 5 ' flank of mouse H19 in an unusual chromatin conformation unidirectionally blocks enhancer-promoter communication

Background: During mouse prenatal development, the neighbouring insulin-lik e growth factor II (Igf2) and H19 loci are expressed monoallelically from t he paternal and maternal alleles, respectively. Identical spatiotemporal ex pression patterns and enhancer deletion experiments show that the Igf2 and H19 genes share a common set of enhancers. Deletion of a differentially met hylated region in the 5' flank of the H19 gene partially relieves the repre ssion of the maternal Igf2 and paternal H19 alleles in the soma. The mechan isms underlying the function of the 5' flank of the H19 gene are, however, unknown. Results: Chromatin analysis showed that the 5' flank of the mouse H19 gene contains maternal-specific, multiple nuclease hypersensitive sites that map to linker regions between positioned nucleosomes. These features could be recapitulated in an episomal-based H19 minigene, which was propagated in hu man somatic cells. Although the 5' flank of the H19 promoter has no intrins ic silencer activity under these conditions, it unidirectionally extinguish ed promoter-enhancer communications in a position-dependent manner, without directly affecting the enhancer function. Conclusions: The unmethylated 5' flank of the H19 gene adopts an unusual an d maternal-specific chromatin conformation in somatic cells and regulates e nhancer-promoter communications, thereby providing an explanation for its r ole in manifesting the repressed state of the maternally inherited Igf2 all ele.