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Molecular and Cellular Biology, November 2003, p. 7585-7599, Vol. 23, No. 21
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.21.7585-7599.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Identification of a TAL1 Target Gene Reveals a Positive Role for the LIM Domain-Binding Protein Ldb1 in Erythroid Gene Expression and Differentiation

Zhixiong Xu,1 Suming Huang,1 Long-Sheng Chang,2 Alan D. Agulnick,3 and Stephen J. Brandt1,4,5,6,7*

Departments of Medicine,1 Cell and Developmental Biology,4 Cancer Biology,5 Vanderbilt-Ingram Cancer Center, Vanderbilt University,6 VA Tennessee Valley Healthcare System, Nashville, Tennessee 37232,7 Department of Pediatrics, Children's Hospital and The Ohio State University, Columbus, Ohio 43205,2 CyThera Inc., San Diego, California 921213

Received 7 April 2003/ Returned for modification 20 May 2003/ Accepted 25 July 2003

The TAL1 (or SCL) gene, originally identified from its involvement by a recurrent chromosomal translocation, encodes a basic helix-loop-helix transcription factor essential for erythropoiesis. Although presumed to regulate transcription, its target genes are largely unknown. We show here that a nuclear complex containing TAL1, its DNA-binding partner E47, zinc finger transcription factor GATA-1, LIM domain protein LMO2, and LIM domain-binding protein Ldb1 transactivates the protein 4.2 (P4.2) gene through two E box GATA elements in its proximal promoter. Binding of this complex to DNA was dependent on the integrity of both E box and GATA sites and was demonstrated to occur on the P4.2 promoter in cells. Maximal transcription in transiently transfected cells required both E box GATA elements and expression of all five components of the complex. This complex was shown, in addition, to be capable of linking in solution double-stranded oligonucleotides corresponding to the two P4.2 E box GATA elements. This DNA-linking activity required Ldb1 and increased with dimethyl sulfoxide-induced differentiation of murine erythroleukemia (MEL) cells. In contrast, enforced expression in MEL cells of dimerization-defective mutant Ldb1, as well as wild-type Ldb1, significantly decreased E box GATA DNA-binding activities, P4.2 promoter activity, and accumulation of P4.2 and ß-globin mRNAs. These studies define a physiologic target for a TAL1- and GATA-1-containing ternary complex and reveal a positive role for Ldb1 in erythroid gene expression and differentiation.

* Corresponding author. Mailing address: Division of Hematology-Oncology, Room 777 Preston Research Building, Vanderbilt University Medical Center, Nashville, TN 37232. Phone: (615) 936-1809. Fax: (615) 936-3853. E-mail: stephen.brandt{at}vanderbilt.edu.

Molecular and Cellular Biology, November 2003, p. 7585-7599, Vol. 23, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.21.7585-7599.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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