Transcriptome Analysis of CD4+ T Cells in Coeliac Disease Reveals Imprint of BACH2 and IFNγ Regulation
Open Access
- 7 October 2015
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 10 (10), e0140049
- https://doi.org/10.1371/journal.pone.0140049
Abstract
Genetic studies have to date identified 43 genome wide significant coeliac disease susceptibility (CD) loci comprising over 70 candidate genes. However, how altered regulation of such disease associated genes contributes to CD pathogenesis remains to be elucidated. Recently there has been considerable emphasis on characterising cell type specific and stimulus dependent genetic variants. Therefore in this study we used RNA sequencing to profile over 70 transcriptomes of CD4+ T cells, a cell type crucial for CD pathogenesis, in both stimulated and resting samples from individuals with CD and unaffected controls. We identified extensive transcriptional changes across all conditions, with the previously established CD gene IFNy the most strongly up-regulated gene (log2 fold change 4.6; Padjusted = 2.40x10-11) in CD4+ T cells from CD patients compared to controls. We show a significant correlation of differentially expressed genes with genetic studies of the disease to date (Padjusted = 0.002), and 21 CD candidate susceptibility genes are differentially expressed under one or more of the conditions used in this study. Pathway analysis revealed significant enrichment of immune related processes. Co-expression network analysis identified several modules of coordinately expressed CD genes. Two modules were particularly highly enriched for differentially expressed genes (P-16) and highlighted IFNy and the genetically associated transcription factor BACH2 which showed significantly reduced expression in coeliac samples (log2FC -1.75; Padjusted = 3.6x10-3) as key regulatory genes in CD. Genes regulated by BACH2 were very significantly over-represented among our differentially expressed genes (P-16) indicating that reduced expression of this master regulator of T cell differentiation promotes a pro-inflammatory response and strongly corroborates genetic evidence that BACH2 plays an important role in CD pathogenesis.Keywords
This publication has 70 references indexed in Scilit:
- TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusionsGenome Biology, 2013
- Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk predictionMolecular Psychiatry, 2012
- Nomenclature and listing of celiac disease relevant gluten T-cell epitopes restricted by HLA-DQ moleculesImmunogenetics, 2012
- Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac diseaseNature Genetics, 2011
- Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility lociNature Genetics, 2010
- A CD8+ T cell transcription signature predicts prognosis in autoimmune diseaseNature Medicine, 2010
- Multiple common variants for celiac disease influencing immune gene expressionNature Genetics, 2010
- Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk lociNature Genetics, 2008
- Newly identified genetic risk variants for celiac disease related to the immune responseNature Genetics, 2008
- Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetesNature Genetics, 2007