Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
Program in Biochemistry and Molecular Biophysics, California Institute of Technology, Pasadena, CA, USA.
Nat Immunol. 2023 Sep;24(9):1458-1472. doi: 10.1038/s41590-023-01585-z. Epub 2023 Aug 10.
Runx factors are essential for lineage specification of various hematopoietic cells, including T lymphocytes. However, they regulate context-specific genes and occupy distinct genomic regions in different cell types. Here, we show that dynamic Runx binding shifts in mouse early T cell development are mostly not restricted by local chromatin state but regulated by Runx dosage and functional partners. Runx cofactors compete to recruit a limited pool of Runx factors in early T progenitor cells, and a modest increase in Runx protein availability at pre-commitment stages causes premature Runx occupancy at post-commitment binding sites. This increased Runx factor availability results in striking T cell lineage developmental acceleration by selectively activating T cell-identity and innate lymphoid cell programs. These programs are collectively regulated by Runx together with other, Runx-induced transcription factors that co-occupy Runx-target genes and propagate gene network changes.
Runx 因子对于各种造血细胞的谱系特化是必不可少的，包括 T 淋巴细胞。然而，它们在不同的细胞类型中调节特定于上下文的基因并占据不同的基因组区域。在这里，我们表明，在小鼠早期 T 细胞发育中，Runx 结合的动态变化主要不受局部染色质状态的限制，而是受 Runx 剂量和功能伙伴的调节。Runx 辅助因子竞争以在早期 T 祖细胞中募集有限的 Runx 因子池，在预先承诺阶段 Runx 蛋白可用性的适度增加导致在承诺后结合位点处过早的 Runx 占据。这种增加的 Runx 因子可用性通过选择性激活 T 细胞身份和先天淋巴细胞程序导致显著的 T 细胞谱系发育加速。这些程序由 Runx 与其他 Runx 诱导的转录因子共同调节，这些转录因子共同占据 Runx 靶基因并传播基因网络变化。
