Alternative splicing and transcriptome profiling of experimental autoimmune encephalomyelitis using genome-wide exon arrays.
BACKGROUND
Multiple Sclerosis (MS) is a chronic inflammatory disease causing demyelination and nerve loss in the central nervous system. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS that is widely used to investigate complex pathogenic mechanisms. Transcriptional control through isoform selection and mRNA levels determines pathway activation and ultimately susceptibility to disease.


RESULTS
We have studied the role of alternative splicing and differential expression in lymph node cells from EAE-susceptible Dark Agouti (DA) and EAE-resistant Piebald Virol Glaxo.AV1 (PVG) inbred rat strains using Affymetrix Gene Chip Rat Exon 1.0 ST Arrays. Comparing the two strains, we identified 11 differentially spliced and 206 differentially expressed genes at day 7 post-immunization, as well as 9 differentially spliced and 144 differentially expressed genes upon autoantigen re-stimulation. Functional clustering and pathway analysis implicate genes for glycosylation, lymphocyte activation, potassium channel activity and cellular differentiation in EAE susceptibility.


CONCLUSIONS
Our results demonstrate that alternative splicing occurs during complex disease and may govern EAE susceptibility. Additionally, transcriptome analysis not only identified previously defined EAE pathways regulating the immune system, but also novel mechanisms. Furthermore, several identified genes overlap known quantitative trait loci, providing novel causative candidate targets governing EAE.
Gillett
Alan
A
Department of Clinical Neuroscience, Karolinska Institutet, Neuroimmunology Unit, Center for Molecular Medicine, Karolinska Hospital at Solna, Stockholm, Sweden. Alan.Gillett@ki.se
Maratou
Klio
K
Fewings
Chris
C
Harris
Robert A
RA
Jagodic
Maja
M
Aitman
Tim
T
Olsson
Tomas
T
D017398:Alternative Splicing; D000818:Animals; D002454:Cell Differentiation; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000378:metabolism*; D005091:Exons; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D020869:Gene Expression Profiling; D007249:Inflammation; D008198:Lymph Nodes / Q000473:pathology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats