Role of topoisomerase IIβ in the expression of developmentally regulated genes
Role of topoisomerase IIβ in the expression of developmentally regulated genes
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DOI：
10.1128/mcb.00617-06
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发表时间：
2006-11-01
影响因子：
5.3
通讯作者：
Liu, Leroy F.
中科院分区：
文献类型：
--
作者：
Lyu, Yi Lisa;Lin, Chao-Po;Liu, Leroy F.
已知缺乏拓扑异构酶II β（TopII β）的小鼠表现出围产期死亡表型。在目前的研究中，野生型和top2 β基因敲除小鼠胚胎的大脑的转录谱被生成。令人惊讶的是，在前2个β基因敲除胚胎中，只有少数（1 - 4%）基因受到影响。然而，近30%的发育调控基因的表达上调或下调。相比之下，编码一般细胞生长功能和早期分化标志物的基因的表达不受影响，这表明TopII β不是早期分化编程所需的，而是分化后期发育调控基因表达所需的。与这一概念相一致，脑切片的免疫组织化学分析表明，TopII β和组蛋白去乙酰化酶2，一种已知的TopII β相互作用蛋白，优先表达在分化后期的神经元中。对发育中大脑的染色质免疫沉淀分析揭示了TopII β与许多TopII β敏感基因的5'区域结合。对TopII β敏感基因Kcnd 2的进一步研究揭示了TopII β在转录单位中的存在，其主要结合在启动子区域附近。总之，这些结果支持TopII β在神经元分化晚期激活/抑制发育调控基因中的作用。
Mice lacking topoisomerase II beta (TopII beta) are known to exhibit a perinatal death phenotype. In the current study, transcription profiles of the brains of wild-type and top2 beta knockout mouse embryos were generated. Surprisingly, only a small number (1 to 4%) of genes were affected in top2 beta knockout embryos. However, the expression of nearly 30% of developmentally regulated genes was either up- or down-regulated. By contrast, the expression of genes encoding general cell growth functions and early differentiation markers was not affected, suggesting that TopII beta is not required for early differentiation programming but is specifically required for the expression of developmentally regulated genes at later stages of differentiation. Consistent with this notion, immunohistochemical analysis of brain sections showed that TopII beta and histone deacetylase 2, a known TopII beta-interacting protein, were preferentially expressed in neurons which are in their later stages of differentiation. Chromatin immunoprecipitation analysis of the developing brains revealed TopII beta binding to the 5' region of a number of TopII beta-sensitive genes. Further studies of a TopII beta-sensitive gene, Kcnd2, revealed the presence of TopII beta in the transcription unit with major binding near the promoter region. Together, these results support a role of TopII beta in activation/repression of developmentally regulated genes at late stages of neuronal differentiation.