Network analysis of transcriptional regulation in response to intramuscular interferon-β-1a multiple sclerosis treatment.
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.
Leibniz Institute for Natural Product Research and Infection Biology-Hans-Knoell-Institute, Jena, Germany. michael.hecker@rocketmail.com
M
M
Hecker
R H
RH
Goertsches
C
C
Fatum
D
D
Koczan
H-J
HJ
Thiesen
R
R
Guthke
U K
UK
Zettl
D000328:Adult; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D007273:Injections, Intramuscular; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D014158:Transcription, Genetic
D016899:Interferon-beta; D000068556:Interferon beta-1a