Interplay of bromodomain and histone acetylation in the regulation of p300-dependent genes
Interplay of bromodomain and histone acetylation in the regulation of p300-dependent genes
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DOI：
10.4161/epi.5.6.12224
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发表时间：
2010-08-16
期刊：
影响因子：
3.7
通讯作者：
Li, Qiao
中科院分区：
文献类型：
--
作者：
Chen, Jihong;Ghazawi, Feras M.;Li, Qiao
布罗莫结构域是在包括p300在内的许多转录激活因子中发现的进化上保守的基序，其含有内在的组蛋白乙酰转移酶活性并且是许多转录因子的通用共激活因子。布罗莫结构域作用的一种模式是在染色质重塑和转录激活期间充当识别组蛋白的特异性乙酰基-赖氨酸残基的结合模块。p300的功能是多种基因表达所必需的。然而，目前尚不清楚p300布罗莫结构域是否参与所有或仅一部分p300依赖性基因的表达。在这项研究中，我们研究了野生型或溴缺陷型p300对几个p300依赖基因表达的影响。组蛋白乙酰化对这些基因表达的影响也通过用抑制剂方法靶向组蛋白去乙酰化酶活性来评估。我们发现，这些抑制剂对p300依赖性基因的转录激活的影响在含有溴缺陷型p300的细胞中受损，这表明p300依赖性基因转录中p300和组蛋白乙酰化的相互作用需要溴结构域。我们还观察到溴缺陷型p300在转录水平上的表达增加，可能是为了补偿p300功能的丧失。然而，高水平的溴缺陷p300不能维持组蛋白乙酰化的基础水平。因此，溴结构域对于p300维持组蛋白乙酰化的基础水平和诱导p300依赖性基因的转录激活是重要的。然而，在p300依赖性基因转录中，溴结构域和组蛋白乙酰化的需要由基因特异性方式决定。
The bromodomain is an evolutionarily conserved motif found in many transcriptional activators including p300 which contains an intrinsic histone acetyltransferase activity and is a general coactivator for many transcription factors. One mode of bromodomain action is to serve as a binding module to recognize specific acetyl-lysine residue of histones during chromatin remodeling and transcriptional activation. The function of p300 is required for diverse sets of gene expression. However, it is not known whether the p300 bromodomain is involved in the expression of all or only subset of p300-dependent genes. In this study, we examined the impact of either a wild type or a bromo-deficient p300 on the expression of several p300-dependant genes. The effects of histone acetylation on the expression of these genes were also assessed by targeting histone deacetylase activities with an inhibitor approach. We show that the impact of these inhibitors on the transcriptional activation of p300-dependent genes is impaired in cells containing the bromo-deficient p300, indicating that the interplay of p300 and histone acetylation in p300-dependent gene transcription requires the bromodomain. We also observed an increase in the expression of bromo-deficient p300 at the level of transcription possibly to compensate for the loss of p300 function. However, the high level of bromo-deficient p300 is not able to maintain the basal level of histone acetylation. Thus, the bromodomain is important for p300 to maintain the basal level of histone acetylation and to induce the transcriptional activation of p300-dependent genes. Nevertheless, the requirement of bromodomain and histone acetylation in p300-dependent gene transcription is determined by a gene specific manner.