Setting up and maintaining differential insulators and boundaries for genomic imprinting.

It is becoming increasingly clear that gene expression is strongly regulated by the surrounding chromatin and nuclear environment. Gene regulatory elements can influence expression over long distances and the genome needs mechanisms whereby transcription can be contained. Our current understanding of the mechanisms whereby insulator/boundary elements organise the genome into active and silent domains is based on chromatin looping models that separate genes and regulatory elements. Imprinted genes have parent-of-origin specific chromatin conformation that seems to be maintained in somatic tissues and reprogrammed in the germline. This review focuses on the proteins found to be present at insulator/boundary sequences at imprinted genes and examines the experimental evidence at the IGF2-H19 locus for a model in which CTCF or other proteins determine primary looping scaffolds that are maintained in most cell lineages and speculates how these loops may enable dynamic secondary associations that can activate or silence genes.

Murrell A 《-》

Epigenetic regulation of Igf2/H19 imprinting at CTCF insulator binding sites.

The mouse insulin-like growth factor II (Igf2) and H19 genes are located adjacent to each other on chromosome 7q11-13 and are reciprocally imprinted. It is believed that the allelic expression of these two genes is regulated by the binding of CTCF insulators to four parent-specific DNA methylation sites in an imprinting control center (ICR) located between these two genes. Although monoallelically expressed in peripheral tissues, Igf2 is biallelically transcribed in the CNS. In this study, we examined the allelic DNA methylation and CTCF binding in the Igf2/H19 imprinting center in CNS, hypothesizing that the aberrant CTCF binding as one of the mechanisms leads to biallelic expression of Igf2 in CNS. Using hybrid F1 mice (M. spretus males x C57BL/6 females), we showed that in CNS, CTCF binding sites in the ICR were methylated exclusively on the paternal allele, and CTCF bound only to the unmethylated maternal allele, showing no differences from the imprinted peripheral tissues. Among three other epigenetic modifications examined, histone H3 lysine 9 methylation correlated well with Igf2 allelic expression in CNS. These results suggest that CTCF binding to the ICR alone is not sufficient to insulate the Igf2 maternal promoter and to regulate the allelic expression of the gene in the CNS, thus challenging the aberrant CTCF binding as a common mechanism for lack of Igf2 imprinting in CNS. Further studies should be focused on the identification of factors that are involved in histone methylation and CTCF-associated factors that may be needed to coordinate Igf2 imprinting.

Yang Y ，Hu JF ，Ulaner GA ，Li T ，Yao X ，Vu TH ，Hoffman AR ... -  《JOURNAL OF CELLULAR BIOCHEMISTRY》

CTCF-dependent chromatin insulator is linked to epigenetic remodeling.

Ishihara K ，Oshimura M ，Nakao M 《MOLECULAR CELL》

Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene.

Bell AC ，Felsenfeld G 《NATURE》

CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus.

Hark AT ，Schoenherr CJ ，Katz DJ ，Ingram RS ，Levorse JM ，Tilghman SM ... -  《NATURE》