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Molecular and Cellular Biology, November 2009, p. 5900-5910, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.00419-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Defective Erythropoiesis in Transgenic Mice Expressing Dominant-Negative Upstream Stimulatory Factor{triangledown}

Shermi Y. Liang,1,{dagger} Babak Moghimi,1,{dagger} Valerie J. Crusselle-Davis,1 I-Ju Lin,1 Michael H. Rosenberg,1 Xingguo Li,1 John Strouboulis,2 Suming Huang,1,3,4 and Jörg Bungert1,3,4,5*

Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida,1 Institute of Molecular Oncology, BSRC Alexander Fleming, Varkiza, Greece,2 Center for Epigenetics,3 Genetics Institute,4 Powell Gene Therapy Center, University of Florida, Gainesville, Florida5

Received 1 April 2009/ Returned for modification 2 May 2009/ Accepted 16 August 2009

Transcription factor USF is a ubiquitously expressed member of the helix-loop-helix family of proteins. It binds with high affinity to E-box elements and, through interaction with coactivators, aids in the formation of transcription complexes. Previous work demonstrated that USF regulates genes during erythroid differentiation, including HoxB4 and β-globin. Here, we show that the erythroid cell-specific expression of a dominant-negative mutant of USF, A-USF, in transgenic mice reduces the expression of all β-type globin genes and leads to the diminished association of RNA polymerase II with locus control region element HS2 and with the β-globin gene promoter. We further show that the expression of A-USF reduces the expression of several key erythroid cell-specific transcription factors, including EKLF and Tal-1. We provide evidence demonstrating that USF interacts with known regulatory DNA elements in the EKLF and Tal-1 gene loci in erythroid cells. Furthermore, A-USF-expressing transgenic mice exhibit a defect in the formation of CD71+ progenitor and Ter-119+ mature erythroid cells. In summary, the data demonstrate that USF regulates globin gene expression indirectly by enhancing the expression of erythroid transcription factors and directly by mediating the recruitment of transcription complexes to the globin gene locus.

* Corresponding author. Mailing address: Department of Biochemistry, and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610. Phone: (352) 273-8098. Fax: (352) 273-2953. E-mail: jbungert{at}ufl.edu

{triangledown} Published ahead of print on 24 August 2009.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, November 2009, p. 5900-5910, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.00419-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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