The CD4(+) T cell methylome contributes to a distinct CD4(+) T cell transcriptional signature in Mycobacterium bovis-infected cattle.
The CD4(+) T cell methylome contributes to a distinct CD4(+) T cell transcriptional signature in Mycobacterium bovis-infected cattle.
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DOI：
10.1038/srep31014
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发表时间：
2016-08-10
影响因子：
4.6
通讯作者：
Meade KG
中科院分区：
文献类型：
--
作者：
Doherty R;Whiston R;Cormican P;Finlay EK;Couldrey C;Brady C;O'Farrelly C;Meade KG
我们假设，CD 4 + T淋巴细胞的表观遗传调节有助于向功能失调的T细胞表型转变，这可能影响其清除分枝杆菌感染的能力。结合RNA-seq转录组学分析和还原型亚硫酸氢盐测序，在M.感染的牛和健康的牛。196个DMR位于注释基因的10 kb内，包括GATA 3和RORC，这两个基因分别编码促进TH 2和TH 17 T辅助细胞亚群的转录因子。TNFRSF 4和干扰素-γ基因的基因特异性DNA甲基化和基因表达水平显著负相关，表明存在调控关系。DMR的通路分析鉴定了参与抗增殖TGF-β信号通路的基因的富集，并且TB感染牛的外周血白细胞中TGFB 1表达显著增加。牛CD 4 + T细胞甲基化组的首次分析表明，DNA甲基化直接导致了感染M的牛的CD 4 + T细胞中独特的基因表达特征。牛在牛分枝杆菌感染期间，邻近关键炎症基因位点的特异性甲基化变化可能对非保护性CD 4 + T细胞应答的出现至关重要。
We hypothesised that epigenetic regulation of CD4+ T lymphocytes contributes to a shift toward a dysfunctional T cell phenotype which may impact on their ability to clear mycobacterial infection. Combined RNA-seq transcriptomic profiling and Reduced Representation Bisulfite Sequencing identified 193 significantly differentially expressed genes and 760 differentially methylated regions (DMRs), between CD4+ T cells from M. bovis infected and healthy cattle. 196 DMRs were located within 10 kb of annotated genes, including GATA3 and RORC, both of which encode transcription factors that promote TH2 and TH17 T helper cell subsets respectively. Gene-specific DNA methylation and gene expression levels for the TNFRSF4 and Interferon-γ genes were significantly negatively correlated suggesting a regulatory relationship. Pathway analysis of DMRs identified enrichment of genes involved in the anti-proliferative TGF-β signaling pathway and TGFB1 expression was significantly increased in peripheral blood leukocytes from TB-infected cattle. This first analysis of the bovine CD4+ T cell methylome suggests that DNA methylation directly contributes to a distinct gene expression signature in CD4+ T cells from cattle infected with M. bovis. Specific methylation changes proximal to key inflammatory gene loci may be critical to the emergence of a non-protective CD4+ T cell response during mycobacterial infection in cattle.