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Molecular and Cellular Biology, October 2008, p. 6473-6482, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00204-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

CTCF Regulates Allelic Expression of Igf2 by Orchestrating a Promoter-Polycomb Repressive Complex 2 Intrachromosomal Loop

Tao Li,^1,2,¶ Ji-Fan Hu,^1,3*,¶ Xinwen Qiu,² Jianqun Ling,¹ Huiling Chen,¹ Shukui Wang,¹ Aiju Hou,¹ Thanh H. Vu,² and Andrew R. Hoffman^1,2*

Medical Service, VA Palo Alto Health Care System, Palo Alto, California 94304,¹ Department of Medicine, Stanford University Medical School, Palo Alto, California 94034,² GMR Epigenetics Corporation, 3427 Hillview Avenue, Suite 200, Palo Alto, California 94304³

Received 8 February 2008/ Returned for modification 24 March 2008/ Accepted 21 July 2008

CTCF is a zinc finger DNA-binding protein that regulates the epigenetic states of numerous target genes. Using allelic regulation of mouse insulin-like growth factor II (Igf2) as a model, we demonstrate that CTCF binds to the unmethylated maternal allele of the imprinting control region (ICR) in the Igf2/H19 imprinting domain and forms a long-range intrachromosomal loop to interact with the three clustered Igf2 promoters. Polycomb repressive complex 2 is recruited through the interaction of CTCF with Suz12, leading to allele-specific methylation at lysine 27 of histone H3 (H3-K27) and to suppression of the maternal Igf2 promoters. Targeted mutation or deletion of the maternal ICR abolishes this chromatin loop, decreases allelic H3-K27 methylation, and causes loss of Igf2 imprinting. RNA interference knockdown of Suz12 also leads to reactivation of the maternal Igf2 allele and biallelic Igf2 expression. CTCF and Suz12 are coprecipitated from nuclear extracts with antibodies specific for either protein, and they interact with each other in a two-hybrid system. These findings offer insight into general epigenetic mechanisms by which CTCF governs gene expression by orchestrating chromatin loop structures and by serving as a DNA-binding protein scaffold to recruit and bind polycomb repressive complexes.

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* Corresponding author. Mailing address for Ji-Fan Hu: Department of Medicine, PAIRE, VA Palo Alto Health Care System, Palo Alto, CA 94304. Phone: (650) 493-5000, ext. 63175. Fax: (650) 856-8024. E-mail: jifan{at}stanford.edu. Mailing address for Andrew R. Hoffman: Medical Service, VA Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, CA 94304. Phone: (650) 858-3930. Fax: (650) 856-8024. E-mail: arhoffman{at}stanford.edu

Published ahead of print on 28 July 2008.

^¶ Equal contribution to this work.

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Molecular and Cellular Biology, October 2008, p. 6473-6482, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00204-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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