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Molecular and Cellular Biology, October 2006, p. 7056-7067, Vol. 26, No. 19
0270-7306/06/$08.00+0     doi:10.1128/MCB.01033-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Distinct Functions of Dispersed GATA Factor Complexes at an Endogenous Gene Locus

Jeffrey A. Grass,1 Huie Jing,2,{dagger} Shin-Il Kim,1,{dagger} Melissa L. Martowicz,1 Saumen Pal,1 Gerd A. Blobel,2 and Emery H. Bresnick1*

University of Wisconsin Medical School, Department of Pharmacology, 1300 University Avenue, Madison, Wisconsin 53706,1 The Children's Hospital of Pennsylvania, Division of Hematology, Philadelphia, Pennsylvania 191042

Received 8 June 2006/ Accepted 12 July 2006

The reciprocal expression of GATA-1 and GATA-2 during hematopoiesis is an important determinant of red blood cell development. Whereas Gata2 is preferentially transcribed early in hematopoiesis, elevated GATA-1 levels result in GATA-1 occupancy at sites upstream of the Gata2 locus and transcriptional repression. GATA-2 occupies these sites in the transcriptionally active locus, suggesting that a "GATA switch" abrogates GATA-2-mediated positive autoregulation. Chromatin immunoprecipitation (ChIP) coupled with genomic microarray analysis and quantitative ChIP analysis with GATA-1-null cells expressing an estrogen receptor ligand binding domain fusion to GATA-1 revealed additional GATA switches 77 kb upstream of Gata2 and within intron 4 at +9.5 kb. Despite indistinguishable GATA-1 occupancy at –77 kb and +9.5 kb versus other GATA switch sites, GATA-1 functioned uniquely at the different regions. GATA-1 induced histone deacetylation at and near Gata2 but not at the –77 kb region. The –77 kb region, which was DNase I hypersensitive in both active and inactive states, conferred equivalent enhancer activities in GATA-1- and GATA-2-expressing cells. By contrast, the +9.5 kb region exhibited considerably stronger enhancer activity in GATA-2- than in GATA-1-expressing cells, and other GATA switch sites were active only in GATA-1- or GATA-2-expressing cells. Chromosome conformation capture analysis demonstrated higher-order interactions between the –77 kb region and Gata2 in the active and repressed states. These results indicate that dispersed GATA factor complexes function via long-range chromatin interactions and qualitatively distinct activities to regulate Gata2 transcription.

* Corresponding author. Mailing address: University of Wisconsin Medical School, Department of Pharmacology, 1300 University Avenue, Madison, WI 53706. Phone: (608) 265-6446. Fax: (608) 262-1257. E-mail: ehbresni{at}wisc.edu.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, October 2006, p. 7056-7067, Vol. 26, No. 19
0270-7306/06/$08.00+0     doi:10.1128/MCB.01033-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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