title: Transcriptome Analysis of CD4+ T Cells in Coeliac Disease Reveals Imprint of BACH2 and IFNγ Regulation.
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; P(adjusted) = 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 (P(adjusted) = 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<2.2x10(-16)) and highlighted IFNy and the genetically associated transcription factor BACH2 which showed significantly reduced expression in coeliac samples (log2FC -1.75; P(adjusted) = 3.6x10(-3)) as key regulatory genes in CD. Genes regulated by BACH2 were very significantly over-represented among our differentially expressed genes (P<2.2x10(-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.
authors.affiliation: Department of Clinical Medicine, Trinity College Dublin, Trinity Centre, St James's Hospital, Dublin, 8, Ireland.
authors.forename: Emma M
authors.initials: EM
authors.lastname: Quinn
authors.affiliation: Department of Clinical Medicine, Trinity College Dublin, Trinity Centre, St James's Hospital, Dublin, 8, Ireland.
authors.forename: Ciara
authors.initials: C
authors.lastname: Coleman
authors.affiliation: Department of Clinical Medicine, Trinity College Dublin, Trinity Centre, St James's Hospital, Dublin, 8, Ireland.
authors.forename: Ben
authors.initials: B
authors.lastname: Molloy
authors.affiliation: Department of Clinical Medicine, Trinity College Dublin, Trinity Centre, St James's Hospital, Dublin, 8, Ireland.
authors.forename: Patricia
authors.initials: P
authors.lastname: Dominguez Castro
authors.affiliation: Animal and Bioscience Research Department, Grange Research Centre, Teagasc, Dunsany, Ireland.
authors.forename: Paul
authors.initials: P
authors.lastname: Cormican
authors.affiliation: Department of Clinical Medicine, Trinity College Dublin, Trinity Centre, St James's Hospital, Dublin, 8, Ireland.
authors.forename: Valerie
authors.initials: V
authors.lastname: Trimble
authors.affiliation: Department of Clinical Medicine, Trinity College Dublin, Trinity Centre, St James's Hospital, Dublin, 8, Ireland.
authors.forename: Nasir
authors.initials: N
authors.lastname: Mahmud
authors.affiliation: Department of Clinical Medicine, Trinity College Dublin, Trinity Centre, St James's Hospital, Dublin, 8, Ireland.
authors.forename: Ross
authors.initials: R
authors.lastname: McManus
mesh_terms: D000328:Adult; D000368:Aged; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D002446:Celiac Disease / Q000235:genetics* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D017423:Sequence Analysis, RNA; D059467:Transcriptome; D055815:Young Adult
chemical_list: C491123:BACH2 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D007371:Interferon-gamma