TY - JOUR T1 - The Th1 cell regulatory circuitry is largely conserved between human and mouse JF - bioRxiv DO - 10.1101/2021.01.11.426266 SP - 2021.01.11.426266 AU - Stephen Henderson AU - Venu Pullabhatla AU - Arnulf Hertweck AU - Emanuele de Rinaldis AU - Javier Herrero AU - Graham M. Lord AU - Richard G. Jenner Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/01/12/2021.01.11.426266.abstract N2 - Gene expression programmes 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 due to exposure to species-specific pathogens. T-bet (Tbx21) is the immune-specific lineage-defining 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 therefore 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 show that the vast majority of T-bet regulated genes are conserved between mouse and human, either via preservation of a binding site or via an alternative binding site associated with transposon-linked insertion. We also identified genes that are specifically targeted by T-bet in humans or mice and which exhibited species-specific expression. These results provide a genome-wide cross-species comparison of T-bet target gene regulation that will enable more accurate translation of genetic targets and therapeutics from pre-clinical models of inflammatory disease into human clinical trials.Competing Interest StatementThe authors have declared no competing interest. ER -