Open Access Research article

Identification of the Rage-dependent gene regulatory network in a mouse model of skin inflammation

Astrid Riehl1, Tobias Bauer2, Benedikt Brors2, Hauke Busch234, Regina Mark18, Julia Németh1, Christoffer Gebhardt6, Angelika Bierhaus7, Peter Nawroth7, Roland Eils25, Rainer König25, Peter Angel1* and Jochen Hess18

Author Affiliations

1 Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany

2 Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany

3 Freiburg Institute for Advanced Studies - FRIAS School of Life Sciences - LIFENET Albert-Ludwigs-University Freiburg, Germany

4 Center for Biosystems Analysis, Albert-Ludwigs-University Freiburg, Germany

5 Institute of Pharmacy and Molecular Biology and Bioquant Center, University of Heidelberg, Germany

6 Department of Dermatology, University Hospital Heidelberg, Germany

7 Department of Medicine I and Clinical Chemistry, University Hospital Heidelberg, Germany

8 Experimental Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Germany

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BMC Genomics 2010, 11:537  doi:10.1186/1471-2164-11-537

Published: 5 October 2010

Abstract

Background

In the past, molecular mechanisms that drive the initiation of an inflammatory response have been studied intensively. However, corresponding mechanisms that sustain the expression of inflammatory response genes and hence contribute to the establishment of chronic disorders remain poorly understood. Recently, we provided genetic evidence that signaling via the receptor for advanced glycation end products (Rage) drives the strength and maintenance of an inflammatory reaction. In order to decipher the mode of Rage function on gene transcription levels during inflammation, we applied global gene expression profiling on time-resolved samples of mouse back skin, which had been treated with the phorbol ester TPA, a potent inducer of skin inflammation.

Results

Ranking of TPA-regulated genes according to their time average mean and peak expression and superimposition of data sets from wild-type (wt) and Rage-deficient mice revealed that Rage signaling is not essential for initial changes in TPA-induced transcription, but absolutely required for sustained alterations in transcript levels. Next, we used a data set of differentially expressed genes between TPA-treated wt and Rage-deficient skin and performed computational analysis of their proximal promoter regions. We found a highly significant enrichment for several transcription factor binding sites (TFBS) leading to the prediction that corresponding transcription factors, such as Sp1, Tcfap2, E2f, Myc and Egr, are regulated by Rage signaling. Accordingly, we could confirm aberrant expression and regulation of members of the E2f protein family in epidermal keratinocytes of Rage-deficient mice.

Conclusions

In summary, our data support the model that engagement of Rage converts a transient cellular stimulation into sustained cellular dysfunction and highlight a novel role of the Rb-E2f pathway in Rage-dependent inflammation during pathological conditions.