CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France.
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
Nat Commun. 2021 Sep 14;12(1):5446. doi: 10.1038/s41467-021-25758-2.
EOMES and T-BET are related T-box transcription factors that control natural killer (NK) cell development. Here we demonstrate that EOMES and T-BET regulate largely distinct gene sets during this process. EOMES is dominantly expressed in immature NK cells and drives early lineage specification by inducing hallmark receptors and functions. By contrast, T-BET is dominant in mature NK cells, where it induces responsiveness to IL-12 and represses the cell cycle, likely through transcriptional repressors. Regardless, many genes with distinct functions are co-regulated by the two transcription factors. By generating two gene-modified mice facilitating chromatin immunoprecipitation of endogenous EOMES and T-BET, we show a strong overlap in their DNA binding targets, as well as extensive epigenetic changes during NK cell differentiation. Our data thus suggest that EOMES and T-BET may distinctly govern, via differential expression and co-factors recruitment, NK cell maturation by inserting partially overlapping epigenetic regulations.
EOMES 和 T-BET 是相关的 T 盒转录因子，它们控制自然杀伤 (NK) 细胞的发育。在这里，我们证明在这个过程中，EOMES 和 T-BET 调节着截然不同的基因集。EOMES 在未成熟的 NK 细胞中表达占优势，并通过诱导标志性受体和功能驱动早期谱系特异性。相比之下，T-BET 在成熟的 NK 细胞中占主导地位，在那里它诱导对 IL-12 的反应并抑制细胞周期，可能通过转录抑制剂。无论如何，许多具有不同功能的基因都被这两个转录因子共同调控。通过生成两种基因修饰的小鼠，促进内源性 EOMES 和 T-BET 的染色质免疫沉淀，我们显示了它们的 DNA 结合靶标的强烈重叠，以及 NK 细胞分化过程中的广泛表观遗传变化。因此，我们的数据表明，EOMES 和 T-BET 可能通过差异表达和共因子募集，通过插入部分重叠的表观遗传调控，以区分的方式控制 NK 细胞的成熟。
