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Originally published In Press as doi:10.1074/jbc.M011172200 on January 5, 2001

J. Biol. Chem., Vol. 276, Issue 14, 11323-11334, April 6, 2001
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Regulation of an Endogenous Locus Using a Panel of Designed Zinc Finger Proteins Targeted to Accessible Chromatin Regions
ACTIVATION OF VASCULAR ENDOTHELIAL GROWTH FACTOR A*

Pei-Qi LiuDagger , Edward J. RebarDagger , Lei Zhang, Qiang Liu, Andrew C. Jamieson, Yuxin Liang, Hong Qi, Pei-Xiang Li, Bingliang Chen, Matthew C. Mendel, Xiaohong Zhong, Ya-Li Lee, Stephen P. Eisenberg§, S. Kaye Spratt, Casey C. Case, and Alan P. Wolffe

From Sangamo BioSciences Incorporated, Richmond, California 94804

We have mapped conserved regions of enhanced DNase I accessibility within the endogenous chromosomal locus of vascular endothelial growth factor A (VEGF-A). Synthetic zinc finger protein (ZFP) transcription factors were designed to target DNA sequences contained within the DNase I-hypersensitive regions. These ZFPs, when fused to either VP16 or p65 transcriptional activation domains, were able to activate expression of the VEGF-A gene as assayed by mRNA accumulation and VEGF-A protein secretion through a range exceeding that induced by hypoxic stress. Importantly, multiple splice variants of VEGF-A mRNA with defined physiological functions were induced by a single engineered ZFP transcription factor. We present evidence for an enhanced activation of VEGF-A gene transcription by ZFP transcription factors fused to VP16 and p65 targeted to two distinct chromosomal sites >500 base pairs upstream or downstream of the transcription start site. Our strategy provides a novel approach for dissecting the requirements for gene regulation at a distance without altering the DNA sequence of the endogenous target locus.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger These authors contributed equally to this work.

§ Present address: Bolder Biotechnology, Inc., Campus Box 347, C.U.-Boulder, Boulder, CO 80309-0347.

To whom correspondence should be addressed: Sangamo BioSciences Inc., Point Richmond Tech Center, 501 Canal Blvd., Suite A100, Richmond, CA 94804. Tel.: 510-970-6000 (ext. 216); Fax: 510-236-8951; E-mail: awolffe@sangamo.com.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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