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J. Biol. Chem., Vol. 282, Issue 37, 26874-26883, September 14, 2007

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Transcription Factor PU.1 Controls Transcription Start Site Positioning and Alternative TLR4 Promoter Usage^*

Monika Lichtinger, Richard Ingram, Mathias Hornef^¶1, Constanze Bonifer, and Michael Rehli²

From the Department of Hematology and Oncology, University of Regensburg Medical School, 93042 Regensburg, Germany, the ^¶Department for Medical Microbiology and Hygiene, University Clinic of Freiburg, 79104 Freiburg, Germany and the Section of Experimental Haematology, University of Leeds, St James's University Hospital, Leeds LS9 7TF, United Kingdom

Human and mouse show markedly different sensitivities toward bacterial endotoxins, and recent evidence suggests that a species-specific regulation of the lipopolysaccharide receptor Toll-like receptor 4 (Tlr4) may contribute to this phenomenon. To gain further insight into mechanisms of Tlr4 regulation, we conducted a detailed in vivo and in vitro study of the murine Tlr4 gene, including analysis of transcription start site location, transcription factor occupancy, and activities of its proximal regulatory sequences. Our analyses identified a PU.1-dependent myeloid promoter, which is conserved between humans and mouse. We also identified an additional, distal promoter, located 200 bp upstream of the myeloid-specific promoter, which is a functional target of E-box binding factors. In contrast to humans, where non-myeloid cells utilize both promoters, the distal Tlr4 promoter initiates all Tlr4 transcripts in murine non-myeloid cells, indicating that species-specific differences in TLR4 mRNA regulation may primarily exist in non-myeloid cell types. Interestingly, PU.1 null murine myeloid progenitor cells predominantly use the distal promoter, and the conditional induction of PU.1 expression in these cells leads to the rapid switch of transcription initiation to the proximal myeloid promoter. This indicates a direct role for PU.1 in determining the transcriptional start site and in recruiting the basal transcription machinery to myeloid promoters.

Received for publication, May 10, 2007 , and in revised form, June 11, 2007.

^* This work was supported by grants from the City of Hope Medical Center, the Wellcome Trust, the Leukaemia Research Fund, and the Biotechnology and Biological Sciences Research Council (to C. B.) and by Deutsche Forschungsgemeinschaft Grant Re1310/7 (to M. R.). 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.

The on-line version of this article (available at http://www.jbc.org) contains a table and six supplemental figures.

¹ Present address: Hannover Medical School, Medical Microbiology and Hospital Epidemiology, D-30625 Hannover, Germany.

² To whom correspondence should be addressed. Tel.: 49-941-944-5587; Fax: 49-941-944-5593; E-mail: michael.rehli{at}klinik.uni-regensburg.de.

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