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Molecular and Cellular Biology, June 2004, p. 4791-4800, Vol. 24, No. 11
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.11.4791-4800.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Role of CTCF Binding Sites in the Igf2/H19 Imprinting Control Region{dagger}

Piroska E. Szabó,* Shih-Huey E. Tang,{ddagger} Francisco J. Silva, Walter M. K. Tsark, and Jeffrey R. Mann

Division of Biology, Beckman Research Institute of the City of Hope, Duarte, California 91010-3011

Received 17 December 2003/ Returned for modification 11 January 2004/ Accepted 11 March 2004

A ~2.4-kb imprinting control region (ICR) regulates somatic monoallelic expression of the Igf2 and H19 genes. This is achieved through DNA methylation-dependent chromatin insulator and promoter silencing activities on the maternal and paternal chromosomes, respectively. In somatic cells, the hypomethylated maternally inherited ICR binds the insulator protein CTCF at four sites and blocks activity of the proximal Igf2 promoter by insulating it from its distal enhancers. CTCF binding is thought to play a direct role in inhibiting methylation of the ICR in female germ cells and in somatic cells and, therefore, in establishing and maintaining imprinting of the Igf2/H19 region. Here, we report on the effects of eliminating ICR CTCF binding by severely mutating all four sites in mice. We found that in the female and male germ lines, the mutant ICR remained hypomethylated and hypermethylated, respectively, showing that the CTCF binding sites are dispensable for imprinting establishment. Postfertilization, the maternal mutant ICR acquired methylation, which could be explained by loss of methylation inhibition, which is normally provided by CTCF binding. Adjacent regions in cis—the H19 promoter and gene—also acquired methylation, accompanied by downregulation of H19. This could be the result of a silencing effect of the methylated maternal ICR.

* Corresponding author. Mailing address: Division of Biology, Beckman Research Institute of the City of Hope, 1450 East Duarte Rd., Duarte, CA 91010-3011. Phone: (626) 359-8111, ext. 63943. Fax: (626) 358-7703. E-mail: pszabo{at}coh.org.

{dagger} We dedicate this paper to the memory of William Kaplan, pioneer neurogeneticist.

{ddagger} Present address: Department of Biology and Chemistry, Allergan Incorporated, Irvine, CA 92623.

Molecular and Cellular Biology, June 2004, p. 4791-4800, Vol. 24, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.11.4791-4800.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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