Stage-specific action of Runx1 and GATA3 controls silencing of PU.1 expression in mouse pro-T cells.
Stage-specific action of Runx1 and GATA3 controls silencing of PU.1 expression in mouse pro-T cells.
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DOI：
10.1084/jem.20202648
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发表时间：
2021-08-02
期刊：
影响因子：
--
通讯作者：
Rothenberg EV
中科院分区：
文献类型：
--
作者：
Hosokawa H;Koizumi M;Masuhara K;Romero-Wolf M;Tanaka T;Nakayama T;Rothenberg EV
对编码PU1的Spi1的抑制对早期T细胞谱系承诺至关重要，并依赖于GATA3和RUNX1。在承诺过程中，阶段特异性的RUNX1和GATA3结合确定了小鼠SPI1的一个封闭内含子位点，该内含子对SPI1的抑制起到了重要作用。PU.1(SPI1编码)是一种具有多种造血功能的ETS家族转录因子，在胸腺内最早的T细胞前体细胞中高表达，但在T谱系承诺过程中必须下调。转录因子RUNX1和GATA3参与了Spi1的抑制，但时间的基础尚不清楚。我们发现，增加RUNX1和/或GATA3下调Pro-T细胞中Spi1的表达，而在Spi1下调后删除这些因子可重新激活其表达。利用抑制和转录因子结合的阶段特异性，在Spi1内含子2中发现了一个非传统的功能位点。急性Cas9介导的RUNX和GATA基序在该元件中的缺失或破坏重新激活了PRO-T细胞系中沉默的Spi1表达，大大超过了对其他候选元件的干扰，并在承诺过程中抵消了原代PRO-T细胞中Spi1的抑制。因此，RUNX1和GATA3通过小鼠SPI1中的内含子沉默元件特异性地作用于阶段，以控制T谱系承诺期间SPI1抑制的强度和维持。
Repression of Spi1 encoding PU.1 is crucial for early T cell lineage commitment and depends on GATA3 and Runx1. Stage-specific Runx1 and GATA3 binding during commitment identifies a closed intronic site of mouse Spi1 that substantially contributes to Spi1 repression. PU.1 (encoded by Spi1), an ETS-family transcription factor with many hematopoietic roles, is highly expressed in the earliest intrathymic T cell progenitors but must be down-regulated during T lineage commitment. The transcription factors Runx1 and GATA3 have been implicated in this Spi1 repression, but the basis of the timing was unknown. We show that increasing Runx1 and/or GATA3 down-regulates Spi1 expression in pro–T cells, while deletion of these factors after Spi1 down-regulation reactivates its expression. Leveraging the stage specificities of repression and transcription factor binding revealed an unconventional but functional site in Spi1 intron 2. Acute Cas9-mediated deletion or disruption of the Runx and GATA motifs in this element reactivates silenced Spi1 expression in a pro–T cell line, substantially more than disruption of other candidate elements, and counteracts the repression of Spi1 in primary pro–T cells during commitment. Thus, Runx1 and GATA3 work stage specifically through an intronic silencing element in mouse Spi1 to control strength and maintenance of Spi1 repression during T lineage commitment.
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影响因子：
32.4
作者：
Hu G;Cui K;Fang D;Hirose S;Wang X;Wangsa D;Jin W;Ried T;Liu P;Zhu J;Rothenberg EV;Zhao K
通讯作者：
Zhao K
DOI：
10.1038/s41577-020-00426-6
发表时间：
2021-03
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Hosokawa H;Rothenberg EV
通讯作者：
Rothenberg EV
影响因子：
30.5
作者：
Hosokawa H;Romero-Wolf M;Yui MA;Ungerbäck J;Quiloan MLG;Matsumoto M;Nakayama KI;Tanaka T;Rothenberg EV
通讯作者：
Rothenberg EV
影响因子：
10.5
作者：
Champhekar A;Damle SS;Freedman G;Carotta S;Nutt SL;Rothenberg EV
通讯作者：
Rothenberg EV
DOI：
10.4049/jimmunol.1300379
发表时间：
2013-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Furusawa J;Moro K;Motomura Y;Okamoto K;Zhu J;Takayanagi H;Kubo M;Koyasu S
通讯作者：
Koyasu S