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Molecular and Cellular Biology, January 2007, p. 579-594, Vol. 27, No. 2
0270-7306/07/$08.00+0     doi:10.1128/MCB.01192-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Distinct Promoters Mediate the Regulation of Ebf1 Gene Expression by Interleukin-7 and Pax5{triangledown} ,{dagger}

Stephanie Roessler,1 Ildiko Györy,1 Sascha Imhof,1 Mikhail Spivakov,2 Ruth R. Williams,2 Meinrad Busslinger,3 Amanda G. Fisher,2 and Rudolf Grosschedl1*

Max Planck Institute of Immunobiology, Department of Cellular and Molecular Immunology, 79108 Freiburg, Germany,1 MRC Clinical Science Centre, Hammersmith Hospital, London W12 ONN, United Kingdom,2 Institute of Molecular Pathology, Vienna, Austria3

Received 30 June 2006/ Returned for modification 16 August 2006/ Accepted 26 October 2006

Early differentiation of B lymphocytes requires the function of multiple transcription factors that regulate the specification and commitment of the lineage. Loss- and gain-of-function experiments have provided important insight into the transcriptional control of B lymphopoiesis, whereby E2A was suggested to act upstream of EBF1 and Pax5 downstream of EBF1. However, this simple hierarchy cannot account for all observations, and our understanding of a presumed regulatory network, in which transcription factors and signaling pathways operate, is limited. Here, we show that the expression of the Ebf1 gene involves two promoters that are differentially regulated and generate distinct protein isoforms. We find that interleukin-7 signaling, E2A, and EBF1 activate the distal Ebf1 promoter, whereas Pax5, together with Ets1 and Pu.1, regulates the stronger proximal promoter. In the absence of Pax5, the function of the proximal Ebf1 promoter and accumulation of EBF1 protein are impaired and the replication timing and subcellular localization of the Ebf1 locus are altered. Taken together, these data suggest that the regulation of Ebf1 via distinct promoters allows for the generation of several feedback loops and the coordination of multiple determinants of B lymphopoiesis in a regulatory network.

* Corresponding author. Mailing address: Max Planck Institute of Immunobiology, Department of Cellular and Molecular Immunology, 79108 Freiburg, Germany. Phone: 49-761-5108-711. Fax: 49-761-5108-799. E-mail: grosschedl{at}immunbio.mpg.de.

{triangledown} Published ahead of print on 13 November 2006.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, January 2007, p. 579-594, Vol. 27, No. 2
0270-7306/07/$08.00+0     doi:10.1128/MCB.01192-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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