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J. Biol. Chem., Vol. 282, Issue 46, 33336-33345, November 16, 2007

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Critical DNA Binding Interactions of the Insulator Protein CTCF

A SMALL NUMBER OF ZINC FINGERS MEDIATE STRONG BINDING, AND A SINGLE FINGER-DNA INTERACTION CONTROLS BINDING AT IMPRINTED LOCI^*

Mario Renda, Ilaria Baglivo, Bonnie Burgess-Beusse, Sabrina Esposito, Roberto Fattorusso, Gary Felsenfeld¹, and Paolo V. Pedone²

From the Dipartimento di Scienze Ambientali, Seconda Università degli Studi di Napoli via Vivaldi 43, 81100 Caserta, Italy and the Laboratory of Molecular Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892-0540

The DNA-binding protein CTCF (CCCTC binding factor) mediates enhancer blocking insulation at sites throughout the genome and plays an important role in regulating allele-specific expression at the Igf2/H19 locus and at other imprinted loci. Evidence is also accumulating that CTCF is involved in large scale organization of genomic chromatin. Although CTCF has 11 zinc fingers, we show here that only 4 of these are essential to strong binding and that they recognize a core 12-bp DNA sequence common to most CTCF sites. By deleting individual fingers and mutating individual sites, we determined the orientation of binding. Furthermore, we were able to identify the specific finger and its point of DNA interaction that are responsible for the loss of CTCF binding when CpG residues are methylated in the imprinted Igf2/H19 locus. This single interaction appears to be critical for allele-specific binding and insulation by CTCF.

Received for publication, July 27, 2007 , and in revised form, September 7, 2007.

^* This work was supported in part by Grants PRIN 2006 from Ministero dell'Istruzione dell'Università e della Ricerca (MIUR) (to R. F. and P. V. P.), FIRB 2003 from MIUR (to P. V. P.), L. R. N. 5 2003 from Regione Campania (to P. V. P.), and by the Intramural Research Program, NIDDK, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: NIDDK, National Institutes of Health, Bldg. 5, Rm. 212, Bethesda, MD 20892-0540. Tel.: 301-496-4173; Fax: 301-496-0201; E-mail: gary.felsenfeld{at}nih.gov. ² To whom correspondence may be addressed. Tel.: 39-0823-274598; Fax: 39-0823-274605; E-mail: paolov.pedone{at}unina2.it.

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