The transcription factor E2A activates multiple enhancers that drive Rag expression in developing T and B cells
The transcription factor E2A activates multiple enhancers that drive Rag expression in developing T and B cells
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DOI：
10.1126/sciimmunol.abb1455
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发表时间：
2020-09-01
影响因子：
24.8
通讯作者：
Miyazaki, Masaki
中科院分区：
文献类型：
--
作者：
Miyazaki, Kazuko;Watanabe, Hitomi;Miyazaki, Masaki
细胞类型特异性基因的表达是由谱系特异性转录因子和它们所结合的顺式调控元件之间的相互作用驱动的。获得性免疫依赖于RAG介导的T细胞受体(TCR)和免疫球蛋白(Ig)基因的组装。虽然Rag1和Rag2的表达在很大程度上局限于适应性淋巴系细胞，但仍不清楚RAg基因的表达是如何以细胞系特异性的方式调节的。在这里，我们确定了三个不同的顺式调节元件，一个T细胞谱系特异性增强子(R-ten)和两个B细胞特异性元件rib和r2b。通过产生缺乏R-ten或RIB和r2b的小鼠，我们证明了这些不同的调控元件集驱动了发育中的T和B细胞中RAG基因的表达。这些元件的共同点是它们都有结合转录因子E2A的能力。通过产生一个在R-Ten的E2A结合位点内携带突变的小鼠株，我们证明了E2A到这个位点的募集对于协调染色质构象的变化是必不可少的，染色质构象的变化驱动T细胞中RAG基因的表达。通过定位顺式调控元件和产生多个缺乏不同增强子元件的小鼠品系，我们证明了RAG基因在发育中的T和B细胞中的表达是由不同的E2A依赖的顺式调节模块驱动的。
Cell type-specific gene expression is driven by the interplay between lineage-specific transcription factors and cis-regulatory elements to which they bind. Adaptive immunity relies on RAG-mediated assembly of T cell receptor (TCR) and immunoglobulin (Ig) genes. Although Rag1 and Rag2 expression is largely restricted to adaptive lymphoid lineage cells, it remains unclear how Rag gene expression is regulated in a cell lineage-specific manner. Here, we identified three distinct cis-regulatory elements, a T cell lineage-specific enhancer (R-TEn) and the two B cell-specific elements, RIB and R2B. By generating mice lacking either R-TEn or RIB and R2B, we demonstrate that these distinct sets of regulatory elements drive the expression of Rag genes in developing T and B cells. What these elements have in common is their ability to bind the transcription factor E2A. By generating a mouse strain that carries a mutation within the E2A binding site of R-TEn, we demonstrate that recruitment of E2A to this site is essential for orchestrating changes in chromatin conformation that drive expression of Rag genes in T cells. By mapping cis-regulatory elements and generating multiple mouse strains lacking distinct enhancer elements, we demonstrate expression of Rag genes in developing T and B cells to be driven by distinct sets of E2A-dependent cis-regulatory modules.