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The chicken ß-globin insulator element conveys chromatin boundary activity but not imprinting at the mouse Igf2/H19 domain

Piroska E. Szabó, Shih-Huey E. Tang, Michael R. Reed^*, Francisco J. Silva, Walter M. K. Tsark and Jeffrey R. Mann

Division of Biology, Beckman Research Institute of the City of Hope, 1450 East Duarte Road, Duarte, California 91010-3011, USA
^* Present address: Life Sciences Division, Motorola, 757 South Raymond Avenue, Pasadena, California 91105-3250, USA

Author for correspondence

Accepted 26 November 2001

Imprinting of the mouse insulin-like growth factor 2 (Igf2) and H19 genes is regulated by an imprinting control region (ICR). The hypomethylated maternal copy functions as a chromatin insulator through the binding of CTCF and prevents Igf2 activation in cis, while hypermethylation of the paternal copy inactivates insulator function and leads to inactivation of H19 in cis. The specificity of the ICR sequence for mediating imprinting and chromatin insulation was investigated by substituting it for two copies of the chicken ß-globin insulator element, (ChßGI)₂, in mice. This introduced sequence resembles the ICR in size, and in containing CTCF-binding sites and CpGs, but otherwise lacks homology. On maternal inheritance, the (ChßGI)₂ was hypomethylated and displayed full chromatin insulator activity. Monoallelic expression of Igf2 and H19 was retained and mice were of normal size. These results suggest that the ICR sequence, aside from CTCF-binding sites, is not uniquely specialized for chromatin insulation at the Igf2/H19 region. On paternal inheritance, the (ChßGI)₂ was also hypomethylated and displayed strong insulator activity – fetuses possessed very low levels of Igf2 RNA and were greatly reduced in size, being as small as Igf2-null mutants. Furthermore, the paternal H19 allele was active. These results suggest that differential ICR methylation in the female and male germ lines is not acquired through differential binding of CTCF. Rather, it is likely to be acquired through a separate or downstream process.

Key words: Chromatin Insulation, Imprinting, Methylation, Epigenetics, Insulin-like growth factor 2, Gene regulation, Mouse