Abstract
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.
Highlights
Bovine tuberculosis (BTB) is one of the most complex and persistent infections facing the agricultural industry[1]
Absolute lymphocyte numbers were similar between groups, absolute polymorphonuclear neutrophil numbers were depleted in TB infected cattle, relative to healthy control (HC) cattle (Figure S1)
We have identified a distinctive CD4+ T cell transcriptomic signature which clearly segregates BTB infected from HC cattle, indicating clear functional divergence in this key cell subset in response to infection
Summary
Bovine tuberculosis (BTB) is one of the most complex and persistent infections facing the agricultural industry[1]. As a predominant mechanism of epigenetic regulation, DNA methylation causes chemical changes in DNA without alterations in the underlying DNA sequence These changes dictate cellular phenotypes via altered gene expression profiles[14], and as a result can potentially determine the direction and potency of an immune response during mycobacterial infection. While the recent assembly of the bovine genome, followed by technological developments in genomics has accelerated understanding of the pathogenesis of BTB17,18, the role of DNA methylation in regulating the CD4+ T-cell responses during mycobacterial infection in cattle has not been explored. This study focused on identifying differences in the CD4+ T lymphocyte response induced during natural M. bovis infection, using RNA-seq gene expression analysis and sought to determine the regulatory contribution played by the CD4+ T lymphocyte DNA methylome
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