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Molecular and Cellular Biology, April 2005, p. 2832-2845, Vol. 25, No. 7
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.7.2832-2845.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Potential Autoregulation of Transcription Factor PU.1 by an Upstream Regulatory Element

Yutaka Okuno,1,2,{dagger} Gang Huang,1,{dagger} Frank Rosenbauer,1,{dagger} Erica K. Evans,1,{ddagger} Hanna S. Radomska,1 Hiromi Iwasaki,3 Koichi Akashi,3 Francoise Moreau-Gachelin,4 Youlin Li,1,§ Pu Zhang,1 Berthold Göttgens,5 and Daniel G. Tenen1*

Harvard Institutes of Medicine,1 Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts,3 Department of Hematology, Kumamoto University School of Medicine, Kumamoto, Japan,2 Section de Recherche, Institut Curie, INSERM U528, Paris, France,4 Department of Hematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, England5

Received 31 July 2004/ Returned for modification 26 September 2004/ Accepted 15 December 2004

Regulation of the hematopoietic transcription factor PU.1 (Spi-1) plays a critical role in the development of white cells, and abnormal expression of PU.1 can lead to leukemia. We previously reported that the PU.1 promoter cannot induce expression of a reporter gene in vivo, and cell-type-specific expression of PU.1 in stable lines was conferred by a 3.4-kb DNA fragment including a DNase I hypersensitive site located 14 kb upstream of the transcription start site. Here we demonstrate that this kb –14 site confers lineage-specific reporter gene expression in vivo. This kb –14 upstream regulatory element contains two 300-bp regions which are highly conserved in five mammalian species. In Friend virus-induced erythroleukemia, the spleen focus-forming virus integrates into the PU.1 locus between these two conserved regions. DNA binding experiments demonstrated that PU.1 itself and Elf-1 bind to a highly conserved site within the proximal homologous region in vivo. A mutation of this site abolishing binding of PU.1 and Elf-1 led to a marked decrease in the ability of this upstream element to direct activity of reporter gene in myelomonocytic cell lines. These data suggest that a potential positive autoregulatory loop mediated through an upstream regulatory element is essential for proper PU.1 gene expression.

* Corresponding author: Harvard Institutes of Medicine, Room 954, 77 Ave. Louis Pasteur, Boston, MA 02115. Phone: (617) 667-5561. Fax: (617) 667-3299. E-mail: dtenen{at}bidmc.harvard.edu.

{dagger} Y.O., G.H., and F.R. contributed equally to this work.

{ddagger} Present address: GPC Biotech Inc., Waltham, MA 02451.

§ Present address: Bayer Corporation, Tarrytown, NY 10591.

Molecular and Cellular Biology, April 2005, p. 2832-2845, Vol. 25, No. 7
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.7.2832-2845.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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