Regulation of early T-lineage gene expression and developmental progression by the progenitor cell transcription factor PU.1.
Regulation of early T-lineage gene expression and developmental progression by the progenitor cell transcription factor PU.1.
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DOI：
10.1101/gad.259879.115
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发表时间：
2015-04-15
影响因子：
10.5
通讯作者：
Rothenberg EV
中科院分区：
文献类型：
--
作者：
Champhekar A;Damle SS;Freedman G;Carotta S;Nutt SL;Rothenberg EV
在胸腺中，高PU. 1表达在早期阶段的多次细胞分裂中持续存在，但随后在T细胞谱系定型期间急剧下降福尔斯。在这里，Champhekar等人表明，PU.1是完全增殖所必需的，限制了一些非T细胞的命运，并控制了T细胞发育进程的时间。全基因组转录组分析鉴定了影响祖细胞信号传导和细胞生物学的PU.1阳性和PU.1阴性调节的新靶点，并表明对祖细胞转录因子的不同子集的不同调节作用。ETS家族转录因子PU.1对包括T细胞在内的几种血液谱系的发育至关重要，但其在胸腺内T细胞前体中的功能尚不清楚。在胸腺中，高PU. 1表达在早期阶段的多次细胞分裂中持续存在，但随后在T细胞谱系定型期间急剧下降福尔斯。PU.1沉默对T细胞定型至关重要，但PU.1活性如何对T细胞发育产生积极影响仍是未知数。在这里，我们采用了条件性敲除和修饰的拮抗剂PU.1构建体来干扰PU.1功能阶段特异性地在早期T细胞中。我们表明，PU.1是完全增殖所必需的，限制了对一些非T命运的访问，并控制了T细胞发育进程的时间，使得内源性PU.1的去除或拮抗作用允许早熟地进入T细胞分化。显性负效应表明，这种抑制PU.1是间接介导的。全基因组转录组分析鉴定了PU.1正调控和负调控的新靶点，其影响祖细胞信号传导和细胞生物学，并指示对祖细胞转录因子的不同子集的不同调控作用。因此，除了支持早期T细胞增殖外，PU.1还调节核心T谱系发育程序激活的时机。
In the thymus, high PU.1 expression persists through multiple cell divisions in early stages but then falls sharply during T-cell lineage commitment. Here, Champhekar et al. show that PU.1 is needed for full proliferation, restricting access to some non-T fates, and controlling the timing of T-cell developmental progression. Genome-wide transcriptome analysis identifies novel targets of PU.1-positive and PU.1-negative regulation affecting progenitor cell signaling and cell biology and indicating distinct regulatory effects on different subsets of progenitor cell transcription factors. The ETS family transcription factor PU.1 is essential for the development of several blood lineages, including T cells, but its function in intrathymic T-cell precursors has been poorly defined. In the thymus, high PU.1 expression persists through multiple cell divisions in early stages but then falls sharply during T-cell lineage commitment. PU.1 silencing is critical for T-cell commitment, but it has remained unknown how PU.1 activities could contribute positively to T-cell development. Here we employed conditional knockout and modified antagonist PU.1 constructs to perturb PU.1 function stage-specifically in early T cells. We show that PU.1 is needed for full proliferation, restricting access to some non-T fates, and controlling the timing of T-cell developmental progression such that removal or antagonism of endogenous PU.1 allows precocious access to T-cell differentiation. Dominant-negative effects reveal that this repression by PU.1 is mediated indirectly. Genome-wide transcriptome analysis identifies novel targets of PU.1 positive and negative regulation affecting progenitor cell signaling and cell biology and indicating distinct regulatory effects on different subsets of progenitor cell transcription factors. Thus, in addition to supporting early T-cell proliferation, PU.1 regulates the timing of activation of the core T-lineage developmental program.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
DOI：
10.1084/jem.20050075
发表时间：
2005-05-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Dakic A;Metcalf D;Di Rago L;Mifsud S;Wu L;Nutt SL
通讯作者：
Nutt SL
影响因子：
32.4
作者：
Laiosa, Catherine V.;Stadtfeld, Matthias;Graf, Thomas
通讯作者：
Graf, Thomas
影响因子：
12.3
作者：
de la Rica L;Rodríguez-Ubreva J;García M;Islam AB;Urquiza JM;Hernando H;Christensen J;Helin K;Gómez-Vaquero C;Ballestar E
通讯作者：
Ballestar E
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK