Coffee B, Zhang F, Warren S T, Reines D
Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Nat Genet. 1999 May;22(1):98-101. doi: 10.1038/8807.
Mutation of FMR1 results in fragile X mental retardation. The most common FMR1 mutation is expansion of a CGG repeat tract at the 5' end of FMR1, which leads to cytosine methylation and transcriptional silencing. Both DNA methylation and histone deacetylation have been associated with transcriptional inactivity. The finding that the methyl cytosine-binding protein MeCP2 binds to histone deacetylases and represses transcription in vivo supports a model in which MeCP2 recruits histone deacetylases to methylated DNA, resulting in histone deacetylation, chromatin condensation and transcriptional silencing. 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.
FMR1基因突变会导致脆性X智力障碍。最常见的FMR1基因突变是FMR1基因5'端的CGG重复序列扩增，这会导致胞嘧啶甲基化和转录沉默。DNA甲基化和组蛋白去乙酰化都与转录不活跃有关。甲基化胞嘧啶结合蛋白MeCP2在体内与组蛋白去乙酰化酶结合并抑制转录，这一发现支持了一种模型，即MeCP2将组蛋白去乙酰化酶招募到甲基化的DNA上，导致组蛋白去乙酰化、染色质浓缩和转录沉默。在这里，我们证明在正常个体的细胞中，FMR1基因的5'端与乙酰化的组蛋白H3和H4相关联，但在脆性X患者的细胞中乙酰化水平降低。用5-氮杂-2'-脱氧胞苷（5-aza-dC）处理脆性X细胞会导致乙酰化的组蛋白H3和H4与FMR1重新结合以及转录重新激活，而用曲古抑菌素A（TSA）处理则导致几乎完全乙酰化的组蛋白H4与FMR1重新结合且很少有乙酰化的组蛋白H3重新结合，同时未检测到转录。我们的结果首次描述了人类疾病中特定基因座处组蛋白乙酰化的缺失，并增进了对FMR1转录沉默机制的理解。
