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Molecular and Cellular Biology, June 2007, p. 4551-4565, Vol. 27, No. 12
0270-7306/07/$08.00+0     doi:10.1128/MCB.00235-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Dissecting Molecular Steps in Chromatin Domain Activation during Hematopoietic Differentiation{triangledown}

Shin-Il Kim,1 Scott J. Bultman,2 Huie Jing,3 Gerd A. Blobel,3 and Emery H. Bresnick1*

University of Wisconsin School of Medicine, Department of Pharmacology, 1300 University Avenue, 383 Medical Sciences Center, Madison, Wisconsin 53706,1 University of North Carolina—Chapel Hill, Department of Genetics, Chapel Hill, North Carolina 27599,2 The Children's Hospital of Pennsylvania, Division of Hematology, Philadelphia, Pennsylvania 192043

Received 8 February 2007/ Returned for modification 21 March 2007/ Accepted 3 April 2007

GATA factors orchestrate hematopoiesis via multistep transcriptional mechanisms, but the interrelationships and importance of individual steps are poorly understood. Using complementation analysis with GATA-1-null cells and mice containing a hypomorphic allele of the chromatin remodeler BRG1, we dissected the pathway from GATA-1 binding to cofactor recruitment, chromatin loop formation, and transcriptional activation. Analysis of GATA-1-mediated activation of the ß-globin locus, in which GATA-1 assembles dispersed complexes at the promoters and the distal locus control region (LCR), revealed molecular intermediates, including GATA-1-independent and GATA-1-containing LCR subcomplexes, both defective in promoting loop formation. An additional intermediate consisted of an apparently normal LCR complex and a promoter complex with reduced levels of total RNA polymerase II (Pol II) and Pol II phosphorylated at serine 5 of the carboxy-terminal domain. Reduced BRG1 activity solely compromised Pol II and serine 5-phosphorylated Pol II occupancy at the promoter, phenocopying the LCR-deleted mouse. These studies defined a hierarchical order of GATA-1-triggered events at a complex locus and establish a novel mechanism of long-range gene regulation.

* Corresponding author. Mailing address: University of Wisconsin School of Medicine, 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 16 April 2007.

Molecular and Cellular Biology, June 2007, p. 4551-4565, Vol. 27, No. 12
0270-7306/07/$08.00+0     doi:10.1128/MCB.00235-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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