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J. Biol. Chem., Vol. 282, Issue 19, 14665-14674, May 11, 2007

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Context-dependent GATA Factor Function

COMBINATORIAL REQUIREMENTS FOR TRANSCRIPTIONAL CONTROL IN HEMATOPOIETIC AND ENDOTHELIAL CELLS^*

Ryan J. Wozniak¹, Meghan E. Boyer², Jeffrey A. Grass², Youngsook Lee, and Emery H. Bresnick³

From the Departments of Pharmacology and Anatomy, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706

GATA factors are fundamental components of developmentally important transcriptional networks. By contrast to common mechanisms in which transacting factors function directly at promoters, the hematopoietic GATA factors GATA-1 and GATA-2 often assemble dispersed complexes over broad chromosomal regions. For example, GATA-1 and GATA-2 occupy five conserved regions over 100 kb of the Gata2 locus in the transcriptionally repressed and active states, respectively, in erythroid cells. Since it is unknown whether the individual complexes exert qualitatively distinct or identical functions to regulate Gata2 transcription in vivo, we compared the activity of the -3.9 and +9.5 kb sites of the Gata2 locus in transgenic mice. The +9.5 site functioned as an autonomous enhancer in the endothelium and fetal liver of embryonic day 11 embryos, whereas the -3.9 site lacked such activity. Mechanistic studies demonstrated critical requirements for a GATA motif and a neighboring E-box within the +9.5 site for enhancer activity in endothelial and hematopoietic cells. Surprisingly, whereas this GATA-E-box composite motif was sufficient for enhancer activity in an erythroid precursor cell line, its enhancer function in primary human endothelial cells required additional regulatory modules. These results identify the first molecular determinant of Gata2 transcription in vascular endothelium, composed of a core enhancer module active in both endothelial and hematopoietic cells and regulatory modules preferentially required in endothelial cells.

Received for publication, January 26, 2007 , and in revised form, March 7, 2007.

^* This work was supported by National Institutes of Health Grants DK68634 (to E. H. B.) and HL67050 (to Y. S. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ Supported by the National Institutes of Health through National Research Service Award T32-HL07936 from the University of Wisconsin-Madison Cardiovascular Research Center.

² These authors contributed equally to this work.

³ To whom correspondence should be addressed: University of Wisconsin School of Medicine, Dept. of Pharmacology, 1300 University Ave., Madison, WI 53706. Tel.: 608-265-6446; Fax: 608-262-1257; E-mail: ehbresni{at}wisc.edu.

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