Abstract
Gene expression programs controlled by lineage-determining transcription factors are often conserved between species. However, infectious diseases have exerted profound evolutionary pressure, and therefore the genes regulated by immune-specific transcription factors might be expected to exhibit greater divergence. T-bet (Tbx21) is the immune-specific, lineage-specifying transcription factor for T helper type I (Th1) immunity, which is fundamental for the immune response to intracellular pathogens but also underlies inflammatory diseases. We compared T-bet genomic targets between mouse and human CD4+ T cells and correlated T-bet binding patterns with species-specific gene expression. Remarkably, we found that the majority of T-bet target genes are conserved between mouse and human, either via preservation of binding sites or via alternative binding sites associated with transposon-linked insertion. Species-specific T-bet binding was associated with differences in transcription factor-binding motifs and species-specific expression of associated genes. These results provide a genome-wide cross-species comparison of Th1 gene regulation that will enable more accurate translation of genetic targets and therapeutics from pre-clinical models of inflammatory and infectious diseases and cancer into human clinical trials.
Highlights
The differentiation of naıve CD4+ T cells into T helper type 1 (Th1) effector cells tailors the immune response to target intracellular bacteria and viruses [1]
We first identified the genome positions consistently occupied by T-bet in each species at high confidence (q < 0.01 in all replicate ChIP-seq datasets; Fig S1A and Table S2) and identified the subset of these regions that could be compared between species using liftOver [27]
We have determined the degree to which the Th1 cell regulatory circuitry is conserved between human and mouse
Summary
The differentiation of naıve CD4+ T cells into T helper type 1 (Th1) effector cells tailors the immune response to target intracellular bacteria and viruses [1]. T-bet directly activates genes such as those encoding the inflammatory cytokines IFNγ and TNF and the receptors TIM3 (encoded by HAVCR2) and CCR5 [4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14] At these genes, T-bet binds to extended cis-regulatory regions (super-enhancers) [12, 15, 16] and recruits Mediator and P-TEFb to activate transcription [16]. Genetic variation at T-bet binding sites is associated with differences in T-bet occupancy, including at causal variants associated with inflammatory disease [18], suggesting that differences in T-bet binding between individuals directly contributes to disease risk
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