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

• Published in: PloS one Vol. 5; no. 12; p. e14176
• Main Authors: Riveros, Carlos, Mellor, Drew, Gandhi, Kaushal S, McKay, Fiona C, Cox, Mathew B, Berretta, Regina, Vaezpour, S Yahya, Inostroza-Ponta, Mario, Broadley, Simon A, Heard, Robert N, Vucic, Stephen, Stewart, Graeme J, Williams, David W, Scott, Rodney J, Lechner-Scott, Jeanette, Booth, David R, Moscato, Pablo
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.12.2010; Public Library of Science (PLoS)
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Antigens; Bioinformatics; Biomarkers; Blood; Case-Control Studies; Causation; Cohort Studies; Collaboration; Computational Biology/Genomics; Computational Biology/Transcriptional Regulation; Computer engineering; Computer programs; Consortia; Cyclic AMP response element-binding protein; Development; Diabetes; Disease; DNA binding proteins; DNA microarrays; double prime E2F protein; double prime E2F1 protein; E2F protein; E2F1 protein; Female; Gene expression; Gene Expression Profiling; Gene mapping; Genes; Genetics and Genomics/Bioinformatics; Genetics and Genomics/Gene Expression; Genetics and Genomics/Genetics of the Immune System; Genome-Wide Association Study; Genomes; Genomics; Humans; Immunology/Autoimmunity; Immunology/Genetics of the Immune System; Immunology/Leukocyte Signaling and Gene Expression; Interferon; Lymphocytes; Lymphocytes T; Male; Medical research; Medicine; Messenger RNA; Middle Aged; Multiple sclerosis; Multiple Sclerosis - blood; Multiple Sclerosis - metabolism; Nervous system; Neurological Disorders/Multiple Sclerosis and Related Disorders; Oligodendrocytes; Oligodendroglia - cytology; Pathogenesis; RNA, Messenger - metabolism; Rodents; Transcription factors; Transcription Factors - metabolism; YY1 protein; Australia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0014176

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. 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). 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.