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Rasgrf1 Imprinting Is Regulated by a CTCF-Dependent Methylation-Sensitive Enhancer Blocker

Bongjune Yoon ,^1,, Herry Herman,^1,2,3, Benjamin Hu,² Yoon Jung Park,² Anders Lindroth,² Adam Bell,^4, Adam G. West,^4,¶ Yanjie Chang,¹ Aimee Stablewski,¹ Jessica C. Piel,^2,|| Dmitri I. Loukinov,⁵ Victor V. Lobanenkov,⁵ and Paul D. Soloway^1,2*

Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York 14263,¹ Division of Nutritional Sciences, 108 Savage Hall, Cornell University, Ithaca, New York 14853,² Department of Orthopaedic Surgery, School of Medicine, Padjadjaran State University-Hasan Sadikin General Hospital, Bandung, West Java, Indonesia,³ Laboratory of Molecular Biology, NIDDK, NIH, Bethesda, Maryland 20892,⁴ Laboratory of Immunopathology, NIAID, Rockville, Maryland 20852⁵

Received 2 May 2005/ Returned for modification 13 June 2005/ Accepted 3 October 2005

Imprinted methylation of the paternal Rasgrf1 allele in mice occurs at a differentially methylated domain (DMD) 30 kbp 5' of the promoter. A repeated sequence 3' of the DMD regulates imprinted methylation, which is required for imprinted expression. Here we identify the mechanism by which methylation controls imprinting. The DMD is an enhancer blocker that binds CTCF in a methylation-sensitive manner. CTCF bound to the unmethylated maternal allele silences expression. CTCF binding to the paternal allele is prevented by repeat-mediated methylation, allowing expression. Optimal in vitro enhancer-blocking activity requires CTCF binding sites. The enhancer blocker can be bypassed in vivo and imprinting abolished by placing an extra enhancer proximal to the promoter. Together, the repeats and the DMD constitute a binary switch that regulates Rasgrf1 imprinting.

These authors contributed equally and are listed chronologically with respect to their contributions.

Present address: MIT Picower Center, Cambridge, MA 02139.

Present address: Human Genome Sciences, Inc., Rockville, MD 20850.

^¶ Present address: Division of Cancer Sciences and Molecular Pathology, University of Glasgow, Western Infirmary, Glasgow G11 6NT, United Kingdom.

^|| Present address: University of California at Berkeley, Berkeley, CA 94720.

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