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.

中文翻译：

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Th1 细胞调节电路在人和小鼠之间很大程度上是保守的。

受谱系决定转录因子控制的基因表达程序通常在物种之间是保守的。然而，传染病已经施加了巨大的进化压力，因此受免疫特异性转录因子调节的基因可能会表现出更大的差异。T-bet (Tbx21) 是 T 辅助 I 型 (Th1) 免疫的免疫特异性、谱系特异性转录因子，它是对细胞内病原体的免疫反应的基础，也是炎症性疾病的基础。我们比较了小鼠和人类 CD4 ^{+之间的 T-bet 基因组靶标}T 细胞和与物种特异性基因表达相关的 T-bet 结合模式。值得注意的是，我们发现大多数 T-bet 靶基因在小鼠和人类之间是保守的，无论是通过保留结合位点还是通过与转座子连接的插入相关的替代结合位点。物种特异性 T-bet 结合与转录因子结合基序的差异和相关基因的物种特异性表达有关。这些结果提供了 Th1 基因调控的全基因组跨物种比较，这将使遗传靶点和治疗从炎症和传染病和癌症的临床前模型更准确地转化为人类临床试验。