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J. Biol. Chem., Vol. 282, Issue 19, 14194-14204, May 11, 2007

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Regulation of the Interleukin-7 Receptor Promoter by the Ets Transcription Factors PU.1 and GA-binding Protein in Developing B Cells^*

Rodney P. DeKoter¹, Brock L. Schweitzer, Meghana B. Kamath, Darrel Jones, Hiromi Tagoh, Constanze Bonifer, David A. Hildeman^¶, and Kelly J. Huang

From the Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, the ^¶Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, and the Division of Experimental Hematology, LIMM, University of Leeds, St. James University Hospital, Leeds LS9 7TF, United Kingdom

Signaling through the IL-7 receptor (IL-7R) is required for development and maintenance of the immune system. The receptor for IL-7 is heterodimeric, consisting of a common chain (c, encoded by Il2rg) and an subunit (IL-7R, encoded by Il7r). The Il7r gene is expressed specifically in the immune system in a developmental stage-specific manner. It is not known how the Il7r gene is transcriptionally regulated during B cell development. The goal of this study is to elucidate the function of the Il7r promoter region in developing B cells. Using a combination of 5' rapid amplification of cDNA ends analysis, transient transfection assays, and DNase I hypersensitivity mapping, we identified the location of the Il7r promoter. Using a combination of electrophoretic mobility shift analysis, chromatin immunoprecipitation experiments, and RNA interference experiments, we found that the Ets transcription factors PU.1 and GA-binding protein (GABP) activate the Il7r promoter by interacting with a highly conserved Ets binding site. In committed B lineage cells, GABP can promote Il7r transcription in the absence of PU.1. However, the results of retroviral gene transfer experiments suggest that PU.1 is uniquely required to initiate transcription of the Il7r locus at the earliest stages of progenitor B cell generation. In summary, these results suggest that Il7r transcription is regulated by both PU.1 and GABP in developing B cells.

Received for publication, January 12, 2007 , and in revised form, March 1, 2007.

^* This work was supported by National Institutes of Health Grants AI052175 (to R.P.D.) and AI057753 (to D.A.H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 231 Albert Sabin Way, MSB 3256, Cincinnati, OH 45267-0524. E-mail: dekoterp{at}ucmail.uc.edu.

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