Acetylated histones are associated with FMR1 in normal but not fragile X-syndrome cells
Acetylated histones are associated with FMR1 in normal but not fragile X-syndrome cells
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DOI：
10.1038/8807
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发表时间：
1999-05-01
期刊：
影响因子：
30.8
通讯作者：
Reines, D
中科院分区：
文献类型：
--
作者：
Coffee, B;Zhang, FP;Reines, D
FMR 1突变导致脆性X智力低下（1）。最常见的FMR 1突变是FMR 1 5'端CGG重复序列的扩增（参考文献2-4），这导致胞嘧啶甲基化和转录沉默（5，6）。DNA甲基化和组蛋白去乙酰化都与转录失活有关（7-9）。甲基胞嘧啶结合蛋白MeCP 2与组蛋白脱乙酰酶结合并在体内抑制转录的发现（10，11）支持了MeCP 2将组蛋白脱乙酰酶募集至甲基化DNA的模型，导致组蛋白脱乙酰化、染色质缩合和转录沉默（12）。在这里，我们证明了FMR 1的5'端与来自正常个体的细胞中的乙酰化组蛋白H3和H4相关，但是乙酰化在来自脆性X患者的细胞中减少。用5-氮杂-2 '-脱氧胞苷（5-aza-dC）处理脆性X细胞导致乙酰化组蛋白H3和H4与FMR 1的重新结合和转录再激活，而用曲马多他汀A（TSA）处理导致几乎完全乙酰化组蛋白H4和很少乙酰化组蛋白H3与FMR 1的重新结合，以及没有可检测到的转录。我们的研究结果代表了人类疾病中特定位点组蛋白乙酰化缺失的首次描述，并促进了对FMR 1转录沉默机制的理解。
Mutation of FMR1 results in fragile X mental retardation(1). The most common FMR1 mutation is expansion of a CGG repeat tract at the 5' end of FMR1 (refs 2-4), which leads to cytosine methylation and transcriptional silencing(5,6). Both DNA methylation and histone deacetylation have been associated with transcriptional inactivity(7-9). The finding that the methyl cytosine-binding protein MeCP2 binds to histone deacetylases and represses transcription in vivo(10,11) supports a model in which MeCP2 recruits histone deacetylases to methylated DNA, resulting in histone deacetylation, chromatin condensation and transcriptional silencing(12). Here we demonstrate that the 5' end of FMR1 is associated with acetylated histones H3 and H4 in cells from normal individuals, but acetylation is reduced in cells from fragile X patients. Treatment of fragile X cells with 5-aza-2'-deoxycytidine (5-aza-dC) resulted in reassociation of acetylated histones H3 and H4 with FMR1 and transcriptional reactivation, whereas treatment with trichostatin A (TSA) led to almost complete acetylated histone H4 and little acetylated histone H3 reassociation with FMR1, as well as no detectable transcription. Our results represent the first description of loss of histone acetylation at a specific locus in human disease, and advance understanding of the mechanism of FMR1 transcriptional silencing.