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J. Biol. Chem., Vol. 279, Issue 26, 27575-27583, June 25, 2004

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Regulation of Eye Development by Transcription Control of CCCTC Binding Factor (CTCF)^*

Tie Li, Zhenyu Lu, and Luo Lu¶

From the Division of Molecular Medicine, Harbor-UCLA Medical Center, David Geffen School of Medicine, University of California-Los Angeles, Torrance, California 90502 and the Department of Medical Genetics, Shanghai Second Medical University, Shanghai 200025, People's Republic of China

CCCTC binding factor (CTCF), a transcriptional regulator, plays important roles in epigenetics and development. In the present study, we report that overexpression of CTCF in transgenic mice during embryonic development suppresses Pax6 gene expression. This effect causes defects in ocular development that result in microophthalmia. In eye-derived cells transfected with a tetracycline turn-on CTCF system, up-regulation of CTCF expression significantly suppressed Pax6 expression. In contrast, the knockdown of CTCF mRNA resulted in the down-regulation of CTCF protein expression, which in turn enhanced the Pax6 expression. CTCF controls Pax6 transcription by interacting with a repressor element located in the 5'-flanking region upstream of the Pax6 P0 promoter. This interaction suppressed Pax6 gene transcription by blocking the effect of an ectoderm enhancer located 3.5 kb upstream from the P0 promoter. We also found an 80-bp sequence in a region -1.2 kbp upstream from the P0 promoter that contained multiple CTCF binding sites and interacted with nuclear proteins obtained from eye-derived cells forming electrophoretic mobility shift assay complexes with CTCF. We conclude that a novel function of CTCF is to regulate Pax6 transcription by binding to the repressor element, which in turn blocks the effect of the ectoderm enhancer resulting in the inhibition of P0 promoter activity.

Received for publication, December 19, 2003 , and in revised form, March 29, 2004.

^* This work was supported by National Institutes of Health Grants EY12953 and EY15281 (to L. L.) and by the E-Institutes of the Shanghai Municipal Education Commission (to Z. L.). 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.

^¶ To whom correspondence should be addressed: Division of Molecular Medicine, UCLA David Geffen School of Medicine, Harbor-UCLA Medical Center, 1124 W. Carson St., C-2, Torrance, CA 90502-2006. Tel.: 310-787-6853; Fax: 310-222-3781; E-mail: lluou{at}ucla.edu.

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