Department of Genetics, University of Pennsylvania, Philadelphia, Philadelphia, PA, USA.
Institute for Immunology and Immune Health, University of Pennsylvania, Philadelphia, Philadelphia, PA, USA.
Nat Immunol. 2023 Oct;24(10):1698-1710. doi: 10.1038/s41590-023-01599-7. Epub 2023 Aug 17.
In development, pioneer transcription factors access silent chromatin to reveal lineage-specific gene programs. The structured DNA-binding domains of pioneer factors have been well characterized, but whether and how intrinsically disordered regions affect chromatin and control cell fate is unclear. Here, we report that deletion of an intrinsically disordered region of the pioneer factor TCF-1 (termed L1) leads to an early developmental block in T cells. The few T cells that develop from progenitors expressing TCF-1 lacking L1 exhibit lineage infidelity distinct from the lineage diversion of TCF-1-deficient cells. Mechanistically, L1 is required for activation of T cell genes and repression of GATA2-driven genes, normally reserved to the mast cell and dendritic cell lineages. Underlying this lineage diversion, L1 mediates binding of TCF-1 to its earliest target genes, which are subject to repression as T cells develop. These data suggest that the intrinsically disordered N terminus of TCF-1 maintains T cell lineage fidelity.
在发育过程中,先驱转录因子可访问沉默染色质,以揭示特定谱系的基因程序。先驱因子的结构化 DNA 结合结构域已得到很好的描述,但不确定无规卷曲区域是否以及如何影响染色质并控制细胞命运。在这里,我们报告说,先驱因子 TCF-1(称为 L1)的无规卷曲区域的缺失会导致 T 细胞的早期发育受阻。从表达缺乏 L1 的 TCF-1 的祖细胞中发育而来的少数 T 细胞表现出与 TCF-1 缺陷细胞的谱系转换不同的谱系不忠实。从机制上讲,L1 对于 T 细胞基因的激活和 GATA2 驱动基因的抑制是必需的,这些基因通常保留给肥大细胞和树突状细胞谱系。在这种谱系转换的背后,L1 介导了 TCF-1 与其最早靶基因的结合,随着 T 细胞的发育,这些靶基因受到抑制。这些数据表明,TCF-1 的无规卷曲 N 端维持 T 细胞谱系的保真度。
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