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Molecular and Cellular Biology, November 2008, p. 6681-6694, Vol. 28, No. 21
0270-7306/08/$08.00+0     doi:10.1128/MCB.01061-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Molecular Hallmarks of Endogenous Chromatin Complexes Containing Master Regulators of Hematopoiesis{triangledown} ,{dagger}

Ryan J. Wozniak,1,{ddagger} Sunduz Keles,2,3,{ddagger} Jesse J. Lugus,5 Ken H. Young,4 Meghan E. Boyer,1 Tuan M. Tran,1 Kyunghee Choi,5 and Emery H. Bresnick1*

Departments of Pharmacology,1 Biostatistics and Medical Bioinformatics,2 Statistics,3 Pathology, University of Wisconsin School of Medicine and Public Health, 1300 University Avenue, Madison, Wisconsin 53706,4 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 631105

Received 8 July 2008/ Returned for modification 5 August 2008/ Accepted 28 August 2008

Combinatorial interactions among trans-acting factors establish transcriptional circuits that orchestrate cellular differentiation, survival, and development. Unlike circuits instigated by individual factors, efforts to identify gene ensembles controlled by multiple factors simultaneously are in their infancy. A paradigm has emerged in which the important regulators of hematopoiesis GATA-1 and GATA-2 function combinatorially with Scl/TAL1, another key regulator of hematopoiesis. The underlying mechanism appears to involve preferential assembly of a multimeric complex on a composite DNA element containing WGATAR and E-box motifs. Based on this paradigm, one would predict that GATA-2 and Scl/TAL1 would commonly co-occupy such composite elements in cells. However, chromosome-wide analyses indicated that the vast majority of conserved composite elements were occupied by neither GATA-2 nor Scl/TAL1. Intriguingly, the highly restricted set of GATA-2-occupied composite elements had characteristic molecular hallmarks, specifically Scl/TAL1 occupancy, a specific epigenetic signature, specific neighboring cis elements, and preferential enhancer activity in GATA-2-expressing cells. Genes near the GATA-2-Scl/TAL1-occupied composite elements were regulated by GATA-2 or GATA-1, and therefore these fundamental studies on combinatorial transcriptional mechanisms were also leveraged to discover novel GATA factor-mediated cell regulatory pathways.

* Corresponding author. Mailing address: University of Wisconsin School of Medicine and Public Health, Department of Pharmacology, 383 Medical Sciences Center, 1300 University Avenue, Madison, WI 53706. Phone: (608) 265-6446. Fax: (608) 262-1257. E-mail: ehbresni{at}wisc.edu

{triangledown} Published ahead of print on 8 September 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} R.J.W. and S.K. contributed equally to this study.

Molecular and Cellular Biology, November 2008, p. 6681-6694, Vol. 28, No. 21
0270-7306/08/$08.00+0     doi:10.1128/MCB.01061-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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