title: Gender-based blood transcriptomes and interactomes in multiple sclerosis: involvement of SP1 dependent gene transcription.
abstract: In this study we investigated the contribution of gender to global gene expression in peripheral blood mononuclear cells from multiple sclerosis (MS) patients and healthy controls. We observed that, in contrast to the conventional approach, gender-based case-control comparisons resulted in genelists with significantly reduced heterogeneity in human populations. In addition, MS was characterized by significant changes both in the quantity and in the quality of the sex-specific genes. Application of stringent statistics defined gender-based signatures which classified a second independent MS population with high precision. The global unsupervised cluster analyses for 60 subjects showed that 29/31 female and 27/29 male samples were properly identified. Notably, MS was associated in women and in men with distinct gene signatures which however shared several molecular functions, biological processes and interactors. Issues regarding epigenetic control of gene expression appeared as the main common theme for disease, with a central role for the functional modules related to histone deacetylase, NF-kappaB and androgen receptor signaling. Moreover, in silico analyses predicted that the differential expression in MS women and men were depending on the transcription factor SP1. Specific targeting of this pathway by the bis-anthracycline WP631 impaired T cell responses in vitro and in vivo, and reduced the incidence and the severity of experimental autoimmune encephalomyelitis, indicating that SP1 dependent gene transcription sustains neuroinflammation. Thus, the gender-based approach with its reduced heterogeneity and the systems biology tools with the identification of the molecular and functional networks successfully uncovered the differences but also the commonalities associated to multiple sclerosis in women and men. In conclusion, we propose gender-based systems biology as a novel tool to gain fundamental information on disease-associated functional processes.
authors: Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors: Ramesh
authors: R
authors: Menon
authors: Marco
authors: M
authors: Di Dario
authors: Chiara
authors: C
authors: Cordiglieri
authors: Silvia
authors: S
authors: Musio
authors: Loredana
authors: L
authors: La Mantia
authors: Clara
authors: C
authors: Milanese
authors: Anna Luisa
authors: AL
authors: Di Stefano
authors: Massimo
authors: M
authors: Crabbio
authors: Diego
authors: D
authors: Franciotta
authors: Roberto
authors: R
authors: Bergamaschi
authors: Rosetta
authors: R
authors: Pedotti
authors: Enzo
authors: E
authors: Medico
authors: Cinthia
authors: C
authors: Farina
mesh_terms: D000328:Adult; D000818:Animals; D016000:Cluster Analysis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D015203:Reproducibility of Results; D012737:Sex Factors; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic; D059467:Transcriptome
chemical_list: D016329:Sp1 Transcription Factor