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Network analysis of transcriptional regulation in response to intramuscular interferon-β-1a multiple sclerosis treatment

The Pharmacogenomics Journal volume 12, pages 134–146 (2012)Cite this article

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An Erratum to this article was published on 29 March 2011

Abstract

Interferon-β (IFN-β) is one of the major drugs for multiple sclerosis (MS) treatment. The purpose of this study was to characterize the transcriptional effects induced by intramuscular IFN-β-1a therapy in patients with relapsing–remitting form of MS. By using Affymetrix DNA microarrays, we obtained genome-wide expression profiles of peripheral blood mononuclear cells of 24 MS patients within the first 4 weeks of IFN-β administration. We identified 121 genes that were significantly up- or downregulated compared with baseline, with stronger changed expression at 1 week after start of therapy. Eleven transcription factor-binding sites (TFBS) are overrepresented in the regulatory regions of these genes, including those of IFN regulatory factors and NF-κB. We then applied TFBS-integrating least angle regression, a novel integrative algorithm for deriving gene regulatory networks from gene expression data and TFBS information, to reconstruct the underlying network of molecular interactions. An NF-κB-centered sub-network of genes was highly expressed in patients with IFN-β-related side effects. Expression alterations were confirmed by real-time PCR and literature mining was applied to evaluate network inference accuracy.

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Acknowledgements

We deeply thank Peter Lorenz for helpful discussions and our lab assistants Gabriele Gillwaldt, Silvia Dilk, Ina Schröder and Ildikó Tóth for their help in performing the experiments. We are also grateful to study nurse Christa Tiffert for her invaluable contribution. This study was supported by grants from the German Federal Ministry of Education and Research (BMBF, BioChancePlus, 0313692D), and partially funded by Biogen Idec.

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Authors and Affiliations

  1. Leibniz Institute for Natural Product Research and Infection Biology—Hans-Knoell-Institute, Jena, Germany

    M Hecker & R Guthke

  2. University of Rostock, Institute of Immunology, Rostock, Germany

    M Hecker, R H Goertsches, D Koczan & H-J Thiesen

  3. Department of Neurology, University of Rostock, Rostock, Germany

    R H Goertsches, C Fatum & U K Zettl

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  1. M Hecker
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Correspondence to M Hecker.

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Professor Dr Zettl has received research support, as well as speaking fees from Bayer, Biogen Idec, Merck Serono, Sanofi Aventis and Teva. Mr Hecker, Dr Goertsches, Mr Fatum, Dr Koczan, Prof Dr Thiesen and Dr Guthke declare no potential conflict of interest.

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Hecker, M., Goertsches, R., Fatum, C. et al. Network analysis of transcriptional regulation in response to intramuscular interferon-β-1a multiple sclerosis treatment. Pharmacogenomics J 12, 134–146 (2012). https://doi.org/10.1038/tpj.2010.77

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