The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during thymocyte positive selection.
The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during thymocyte positive selection.
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先驱转录因子 Foxa1 和 Foxa2 在胸腺细胞正选择过程中调节选择性 RNA 剪接。
DOI：
10.1242/dev.199754
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发表时间：
2021-08-01
期刊：
影响因子：
--
通讯作者：
Crompton T
中科院分区：
文献类型：
--
作者：
Lau CI;Rowell J;Yanez DC;Solanki A;Ross S;Ono M;Crompton T
在从CD4 + CD8 +双阳性（DP）到单阳性（SP）胸腺细胞的转变过程中的阳性选择期间，TCR信号传导导致适当的MHC限制以及生存和进展的信号。我们表明，先锋转录因子Foxa1和Foxa2在小鼠T细胞阳性选择过程中是调节RNA剪接所必需的，并且Foxa1和Foxa2具有重叠/补偿作用。在DP胸腺细胞中条件性缺失Foxa1和Foxa2会减少CD4SP、CD8SP和外周初始CD4 + T细胞的阳性选择和发育。Foxa1和Foxa2调节许多编码剪接因子和调节因子的基因的表达，包括Mbnl1、H1f0、Sf3b1、Hnrnpa1、Rnpc3、Prpf4b、Prpf40b和Snrpd3。在阳性选择的CD69 + DP细胞内，在双Foxa1/Foxa2条件性敲除中可变RNA剪接失调，导致>850个差异使用的外显子。许多对T细胞发育的这个阶段重要的基因（Ikzf1 - 3、Ptprc、Stat5a、Stat5b、Cd28、Tcf7）以及剪接因子（Hnrnpab、Hnrnpa2b1、Hnrnpu、Hnrnpul1、Prpf8）显示出多个差异使用的外显子。因此，在阳性选择期间需要Foxa1和Foxa2来调节对T细胞发育至关重要的基因的可变剪接，并且通过也调节剪接因子的剪接，它们对可变剪接进行广泛的控制。
总结：先锋转录因子Foxa1和Foxa2在胸腺中T细胞发育过程中的阳性选择期间对于调节RNA剪接是必需的。
During positive selection at the transition from CD4+CD8+ double-positive (DP) to single-positive (SP) thymocyte, TCR signalling results in appropriate MHC restriction and signals for survival and progression. We show that the pioneer transcription factors Foxa1 and Foxa2 are required to regulate RNA splicing during positive selection of mouse T cells and that Foxa1 and Foxa2 have overlapping/compensatory roles. Conditional deletion of both Foxa1 and Foxa2 from DP thymocytes reduced positive selection and development of CD4SP, CD8SP and peripheral naïve CD4+ T cells. Foxa1 and Foxa2 regulated the expression of many genes encoding splicing factors and regulators, including Mbnl1, H1f0, Sf3b1, Hnrnpa1, Rnpc3, Prpf4b, Prpf40b and Snrpd3. Within the positively selecting CD69+DP cells, alternative RNA splicing was dysregulated in the double Foxa1/Foxa2 conditional knockout, leading to >850 differentially used exons. Many genes important for this stage of T-cell development (Ikzf1-3, Ptprc, Stat5a, Stat5b, Cd28, Tcf7) and splicing factors (Hnrnpab, Hnrnpa2b1, Hnrnpu, Hnrnpul1, Prpf8) showed multiple differentially used exons. Thus, Foxa1 and Foxa2 are required during positive selection to regulate alternative splicing of genes essential for T-cell development, and, by also regulating splicing of splicing factors, they exert widespread control of alternative splicing. Summary: The pioneer transcription factors Foxa1 and Foxa2 are required for positive selection during T-cell development in the thymus for regulation of RNA splicing.
影响因子：
7.8
作者：
Wang L;Xiong Y;Bosselut R
通讯作者：
Bosselut R