A Transcription factor map as revealed by a genome-wide gene expression analysis of whole-blood mRNA transcriptome in multiple sclerosis

Carlos Riveros, Drew Mellor, Stephen Vucic, Graeme J. Stewart, David W. Williams, Rodney J. Scott, Jeanette Lechner-Scott, David R. Booth, Pablo Moscato, Melanie Bahlo, Matthew A. Brown, Brian L. Browning, Kaushal S. Gandhi, Sharon R. Browning, Helmut Butzkueven, William M. Carroll, Patrick Danoy, Judith Field, Simon J. Foote, Lyn R. GriffithsAllan G. Kermode, Trevor J. Kilpatrick, Deborah Mason, Fiona C. McKay, Victoria M. Perreau, Mark Slee, Jim Stankovich, Bruce V. Taylor, James Wiley, Matthew B. Cox, Regina Berretta, S. Yahya Vaezpour, Mario Inostroza-Ponta, Simon A. Broadley, Robert N. Heard

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Background: Several lines of evidence suggest that transcription factors are involved in the pathogenesis of Multiple Sclerosis (MS) but complete mapping of the whole network has been elusive. One of the reasons is that there are several clinical subtypes of MS and transcription factors that may be involved in one subtype may not be in others. We investigate the possibility that this network could be mapped using microarray technologies and contemporary bioinformatics methods on a dataset derived from whole blood in 99 untreated MS patients (36 Relapse Remitting MS, 43 Primary Progressive MS, and 20 Secondary Progressive MS) and 45 age-matched healthy controls. Methodology/Principal Findings: We have used two different analytical methodologies: a non-standard differential expression analysis and a differential co-expression analysis, which have converged on a significant number of regulatory motifs that are statistically overrepresented in genes that are either differentially expressed (or differentially co-expressed) in cases and controls (e.g., V$KROX_Q6, p-value <3.31E-6; V$CREBP1_Q2, p-value <9.93E-6, V$YY1_02, p-value <1.65E-5). Conclusions/Significance: Our analysis uncovered a network of transcription factors that potentially dysregulate several genes in MS or one or more of its disease subtypes. The most significant transcription factor motifs were for the Early Growth Response EGR/KROX family, ATF2, YY1 (Yin and Yang 1), E2F-1/DP-1 and E2F-4/DP-2 heterodimers, SOX5, and CREB and ATF families. These transcription factors are involved in early T-lymphocyte specification and commitment as well as in oligodendrocyte dedifferentiation and development, both pathways that have significant biological plausibility in MS causation.
Original languageEnglish
Article number14176
Number of pages28
JournalPLoS ONE
Issue number12
Publication statusPublished - 2010
Externally publishedYes

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Copyright the Author(s) 2010. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.


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