CTCF regulates cell cycle progression of αβ T cells in the thymus
CTCF regulates cell cycle progression of αβ T cells in the thymus
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DOI：
10.1038/emboj.2008.214
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发表时间：
2008-11-05
期刊：
影响因子：
11.4
通讯作者：
Galjart, Niels
中科院分区：
文献类型：
--
作者：
Heath, Helen;de Almeida, Claudia Ribeiro;Galjart, Niels
11 锌指蛋白 CCCTC 结合因子 ( CTCF) 是一种高度保守的蛋白，参与印记、长程染色质相互作用和转录。为了研究其体内功能，我们培育了具有条件性 Ctcf 敲除等位基因的小鼠。与之前的报告一致，我们发现 Ctcf 基因的普遍消除会导致早期胚胎死亡。胸腺细胞中 CTCF 的组织特异性失活会特异性地阻碍 ab T 细胞的分化，并导致小鼠胸腺中晚期双阴性和未成熟单阳性细胞的积累。这些细胞通常较大且循环活跃，并且含有大量的 CTCF。然而，在 Ctcf 敲除动物中，这些细胞很小，并且由于细胞周期蛋白-CDK 抑制剂 p21 和 p27 表达增加而在细胞周期中受阻。综上所述，我们的结果表明，CTCF 的需要呈剂量依赖性，并且参与胸腺中 ab T 细胞的细胞周期进程。我们认为 CTCF 正向调节快速分裂的胸腺细胞的细胞生长，以便在胸腺中的正向和负向选择之前产生适当数量的细胞。
The 11-zinc finger protein CCCTC-binding factor ( CTCF) is a highly conserved protein, involved in imprinting, longrange chromatin interactions and transcription. To investigate its function in vivo, we generated mice with a conditional Ctcf knockout allele. Consistent with a previous report, we find that ubiquitous ablation of the Ctcf gene results in early embryonic lethality. Tissue-specific inactivation of CTCF in thymocytes specifically hampers the differentiation of ab T cells and causes accumulation of late double-negative and immature single-positive cells in the thymus of mice. These cells are normally large and actively cycling, and contain elevated amounts of CTCF. In Ctcf knockout animals, however, these cells are small and blocked in the cell cycle due to increased expression of the cyclin-CDK inhibitors p21 and p27. Taken together, our results show that CTCF is required in a dose-dependent manner and is involved in cell cycle progression of ab T cells in the thymus. We propose that CTCF positively regulates cell growth in rapidly dividing thymocytes so that appropriate number of cells are generated before positive and negative selection in the thymus.