Priming of lineage-specifying genes by Bcl11b is required for lineage choice in post-selection thymocytes.
Priming of lineage-specifying genes by Bcl11b is required for lineage choice in post-selection thymocytes.
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DOI：
10.1038/s41467-017-00768-1
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发表时间：
2017-09-26
影响因子：
16.6
通讯作者：
Taniuchi I
中科院分区：
文献类型：
--
作者：
Kojo S;Tanaka H;Endo TA;Muroi S;Liu Y;Seo W;Tenno M;Kakugawa K;Naoe Y;Nair K;Moro K;Katsuragi Y;Kanai A;Inaba T;Egawa T;Venkatesh B;Minoda A;Kominami R;Taniuchi I
T 谱系定向前体胸腺细胞通过 T 细胞受体 (TCR) 信号介导的命运决定过程进行筛选，以分化为不同的谱系。然而，目前尚不清楚是否需要任何先行事件来将 TCR 信号与控制谱系决定的转录程序结合起来。在这里，我们表明，Bcl11b（称为 T 谱系定型因子）对于 ThPOK 和 Runx3 的正确表达至关重要，ThPOK 和 Runx3 是 CD4 辅助细胞/CD8 细胞毒性谱系选择的中央调节因子。 Bcl11b 的缺失会导致这些因子的随机表达，从而导致与 MHC 的 TCR 限制无关的谱系扰乱。在预选择阶段之前，Bcl11b 对 Thpok 的初始抑制与已知的 Thpok 沉默子无关，并且需要 Bcl11b 蛋白中的最后一个锌指基序，相比之下，这对于 T 谱系定型来说是可有可无的。总的来说，我们的研究结果为 Bcl11b 在启动谱系特异性基因以将 TCR 信号整合到后续转录调控机制中的功能提供了新的线索。 CD4 和 CD8 T 细胞在胸腺中发育，其转录程序分别由 ThPOK 和 Runx3 控制。作者在此表明，ThPOK 和 Runx3 的正确表达以及正确的 CD4/CD8 谱系定型需要由转录因子 Bcl11b 调节的预定型事件。
T-lineage committed precursor thymocytes are screened by a fate-determination process mediated via T cell receptor (TCR) signals for differentiation into distinct lineages. However, it remains unclear whether any antecedent event is required to couple TCR signals with the transcriptional program governing lineage decisions. Here we show that Bcl11b, known as a T-lineage commitment factor, is essential for proper expression of ThPOK and Runx3, central regulators for the CD4-helper/CD8-cytotoxic lineage choice. Loss of Bcl11b results in random expression of these factors and, thereby, lineage scrambling that is disconnected from TCR restriction by MHC. Initial Thpok repression by Bcl11b prior to the pre-selection stage is independent of a known silencer for Thpok, and requires the last zinc-finger motif in Bcl11b protein, which by contrast is dispensable for T-lineage commitment. Collectively, our findings shed new light on the function of Bcl11b in priming lineage-specifying genes to integrate TCR signals into subsequent transcriptional regulatory mechanisms. CD4 and CD8 T cells develop in the thymus with their transcription programs controlled by ThPOK and Runx3, respectively. Here the authors show that a pre-commitment event modulated by the transcription factor, Bcl11b, is required for the proper expression of ThPOK and Runx3 and correct CD4/CD8 lineage commitment.
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DOI：
10.1126/science.1188063
发表时间：
2010-07-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li P;Burke S;Wang J;Chen X;Ortiz M;Lee SC;Lu D;Campos L;Goulding D;Ng BL;Dougan G;Huntly B;Gottgens B;Jenkins NA;Copeland NG;Colucci F;Liu P
通讯作者：
Liu P
影响因子：
30.5
作者：
Kitagawa Y;Ohkura N;Kidani Y;Vandenbon A;Hirota K;Kawakami R;Yasuda K;Motooka D;Nakamura S;Kondo M;Taniuchi I;Kohwi-Shigematsu T;Sakaguchi S
通讯作者：
Sakaguchi S
影响因子：
32.4
作者：
Califano D;Cho JJ;Uddin MN;Lorentsen KJ;Yang Q;Bhandoola A;Li H;Avram D
通讯作者：
Avram D
影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.1073/pnas.1424104112
发表时间：
2015-06-23
影响因子：
11.1
作者：
Lee, Hyung-Ok;He, Xiao;Kappes, Dietmar J.
通讯作者：
Kappes, Dietmar J.