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Molecular and Cellular Biology, February 2008, p. 1124-1135, Vol. 28, No. 3
0270-7306/08/$08.00+0     doi:10.1128/MCB.01361-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

CTCF Is the Master Organizer of Domain-Wide Allele-Specific Chromatin at the H19/Igf2 Imprinted Region{triangledown}

Li Han, Dong-Hoon Lee, and Piroska E. Szabó*

Division of Molecular Biology, Beckman Research Institute of the City of Hope, 1450 East Duarte Road, Duarte, California 91010-3011

Received 28 July 2007/ Returned for modification 31 August 2007/ Accepted 9 November 2007

A paternally methylated imprinting control region (ICR) directs allele-specific expression of the imprinted H19 and Igf2 genes. CTCF protein binding in the ICR is required in the maternal chromosome for insulating Igf2 from the shared enhancers, initiation of the H19 promoter transcription, maintaining DNA hypomethylation, and chromosome loop formation. Using novel quantitative allele-specific chromatin immunoprecipitation-single-nucleotide primer extension assays, we measured the chromatin composition along the H19/Igf2 imprinted domain in cells with engineered mutations at the four ICR-CTCF binding sites. Abolishing CTCF binding in the ICR reduced normally maternal allele-specific H3K9 acetylation and H3K4 methylation at the H19 ICR and promoter/gene body and maternal allele-specific H3K27 trimethylation at the Igf2 P2 promoter and Igf2 differentially methylated regions (DMRs). Paternal H3K27 trimethylation and macroH2A1 became biallelic in the mutant cells at the H19 promoter while paternal H3K9 acetylation and H3K4 methylation became biallelic at the Igf2 DMRs. We provide evidence that CTCF is the single major organizer of allele-specific chromatin composition in this domain. This finding has important implications: (i) for mechanisms of insulation since CTCF regulates chromatin at a distance, involving repression by H3K27 trimethylation at the Igf2 locus independently of repression by DNA hypermethylation; and (ii) for mechanisms of genomic imprinting since point mutations of CTCF binding sites cause domain-wide "paternalization" of the maternal allele's chromatin composition.

* Corresponding author. Mailing address: Division of Molecular 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

{triangledown} Published ahead of print on 26 November 2007.

Molecular and Cellular Biology, February 2008, p. 1124-1135, Vol. 28, No. 3
0270-7306/08/$08.00+0     doi:10.1128/MCB.01361-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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