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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Loss of histone acetyltransferase cofactor transformation/transcription domain-associated protein impairs liver regeneration after toxic injury.
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Loss of histone acetyltransferase cofactor transformation/transcription domain-associated protein impairs liver regeneration after toxic injury.

机译：组蛋白乙酰转移酶辅因子转化/转录结构域相关蛋白的丧失损害了毒性损伤后的肝再生。

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摘要

Organ regeneration after toxin challenge or physical injury requires a prompt and balanced cell-proliferative response; a well-orchestrated cascade of gene expression is needed to regulate transcription factors and proteins involved in cell cycle progression and cell proliferation. After liver injury, cell cycle entry and progression of hepatocytes are believed to require concerted efforts of transcription factors and histone-modifying activities; however, the actual underlying mechanisms remain largely unknown. The purpose of our study was to investigate the role of the histone acetyltransferase (HAT) cofactor transformation/transcription domain-associated protein (TRRAP) and histone acetylation in the regulation of cell cycle and liver regeneration. To accomplish our purpose, we used a TRRAP conditional knockout mouse model combined with toxin-induced hepatic injury. After we treated the mice with a carbon tetrachloride toxin, conditional ablation of the TRRAP gene in those mice severely impaired liver regeneration and compromised cell cycle entry and progression of hepatocytes. Furthermore, loss of TRRAP impaired the induction of early and late cyclins in regenerating livers by compromising histone acetylation and transcription factor binding at the promoters of the cyclin genes. Our results demonstrate that TRRAP and TRRAP/HAT-mediated acetylation play an important role in liver regeneration after toxic injury and provide insight into the mechanism by which TRRAP/HATs orchestrate the expression of the cyclin genes during cell cycle entry and progression.
机译：毒素攻击或身体受伤后的器官再生需要迅速而平衡的细胞增殖反应;需要精心安排的基因表达级联来调节参与细胞周期进程和细胞增殖的转录因子和蛋白质。肝损伤后，细胞周期进入和肝细胞的进展被认为需要转录因子和组蛋白修饰活性的共同努力。但是，实际的基本机制仍然未知。我们研究的目的是研究组蛋白乙酰转移酶（HAT）辅因子转化/转录域相关蛋白（TRRAP）和组蛋白乙酰化在调节细胞周期和肝脏再生中的作用。为了实现我们的目的，我们使用了TRRAP条件性基因敲除小鼠模型并结合了毒素诱导的肝损伤。在我们用四氯化碳毒素处理小鼠后，这些小鼠中TRRAP基因的条件性切除严重损害了肝脏的再生，并损害了细胞周期的进入和肝细胞的进程。此外，TRRAP的丧失通过损害细胞周期蛋白基因启动子处的组蛋白乙酰化和转录因子结合，损害了再生肝脏中早期和晚期细胞周期蛋白的诱导。我们的结果表明，TRRAP和TRRAP / HAT介导的乙酰化在毒性损伤后的肝再生中起着重要作用，并为TRRAP / HATs调控细胞周期进入和发展过程中cyclin基因表达的机制提供了见解。

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