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Transcriptome Analysis of CD4+ T Cells in Coeliac Disease Reveals Imprint of BACH2 and IFNγ Regulation
Quinn, Emma M; Coleman, Ciara; Molloy, Ben; Castro, Patricia Dominguez; Cormican, Paul; Trimble, Valerie; Mahmud, Nasir; McManus, Ross
Data Availability: The raw sequencing reads (FASTQ files) and sequence read counts mapped to UCSC hg19 for each of the 74 transcriptomes sequenced in this study have been deposited at Gene Expression Omnibus (GEO) accession GSE69549. This project was funded by Science Foundation Ireland Grant number 09/IN.1/B2640 to RM. 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<2.2x10-16) 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<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.
Keyword(s): coeliac disease; Pathogenesis; Gene expression; Genetics of disease; Transcriptome analysis; Gene regulation
Publication Date:
2015
Type: Journal article
Peer-Reviewed: Yes
Language(s): English
Institution: Teagasc
Citation(s): Quinn EM, Coleman C, Molloy B, Dominguez Castro P, Cormican P, Trimble V, et al. (2015) Transcriptome Analysis of CD4+ T Cells in Coeliac Disease Reveals Imprint of BACH2 and IFNγ Regulation. PLoS ONE 10(10): e0140049. doi:10.1371/journal.pone.0140049
1932-6203
Publisher(s): PLOS
First Indexed: 2015-12-01 06:06:49 Last Updated: 2015-12-01 06:06:49