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

Yutaka Okuno,^1,2, Gang Huang,^1, Frank Rosenbauer,^1, Erica K. Evans,^1, 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. Tenen^1*

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.

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

Present address: GPC Biotech Inc., Waltham, MA 02451.

Present address: Bayer Corporation, Tarrytown, NY 10591.

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