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Blood, 5 March 2009, Vol. 113, No. 10, pp. 2191-2201.
Prepublished online as a Blood First Edition Paper on November 14, 2008; DOI 10.1182/blood-2008-07-169417.
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Submitted July 18, 2008
Accepted November 7, 2008
SCL and associated proteins distinguish active from
repressive GATA transcription factor complexes
Tamara Tripic, Wulan Deng, Yong Cheng, Ying Zhang, Christopher R Vakoc, Gregory D Gregory, Ross C Hardison, and Gerd A Blobel*
Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
Department of Biology, University of Pennsylvania, Philadelphia, PA, United States
Center for Comparative Genomics and Bioinformatics, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, United States
University of Pennsylvania School of Medicine, Philadelphia, PA, United States
* Corresponding author; email: blobel{at}email.chop.edu.
GATA-1 controls hematopoietic development by activating and repressing gene transcription, yet the in vivo mechanisms that specify these opposite activities are unknown. By examining the composition of GATA-1 associated protein complexes in a conditional erythroid rescue system as well as through the use of tiling arrays we detected the SCL/TAL1, LMO2, Ldb1, E2A complex at all positively acting GATA-1-bound elements examined. Similarly, the SCL complex is present at all activating GATA elements in megakaryocytes and mast cells. In striking contrast, at sites where GATA-1 functions as a repressor, the SCL complex is depleted. A DNA-binding defective form of SCL maintains association with a subset of active GATA elements indicating that GATA-1 is a key determinant for SCL recruitment. Knockdown of LMO2 selectively impairs activation but not repression by GATA-1. ETO-2, an SCL-associated protein with the potential for transcription repression is also absent from GATA-1-repressed genes but, unlike SCL, fails to accumulate at GATA-1 activated genes. Together, these studies identify the SCL complex as a critical and consistent determinant of positive GATA-1 activity in multiple GATA-1-regulated hematopoietic cell lineages.
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