Genome-wide analysis of histone lysine methylation variations caused by diabetic conditions in human monocytes
Genome-wide analysis of histone lysine methylation variations caused by diabetic conditions in human monocytes
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DOI：
10.1074/jbc.m609446200
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发表时间：
2007-05-04
影响因子：
4.8
通讯作者：
Natarajan, Rama
中科院分区：
文献类型：
--
作者：
Miao, Feng;Wu, Xiwei;Natarajan, Rama
异常的组蛋白赖氨酸甲基化模式改变染色质结构，可以促进基因转录失调和疾病进展。糖尿病的情况，如高血糖(HG)，众所周知会改变关键的病理途径。然而，它们对细胞组蛋白赖氨酸甲基化的影响尚不清楚。我们推测慢性HG可在靶细胞内诱导组蛋白H3、赖氨酸4和赖氨酸9二甲基化(H3K4me2和H3K9me2)的异常改变。染色质免疫沉淀与微阵列相连(芯片上芯片)是目前广泛使用的获取全基因组组蛋白修饰信息的方法。我们采用这种方法来分析和比较在正常葡萄糖和HG中培养的THP-1单核细胞中人类基因编码区和CpG岛区H3K4me2和H3K9me2的变异。随后，我们确定了H3K4me2和H3K9me2在HG和正常血糖中的差异变化的关键相关候选基因，并用后续的常规芯片进行了验证。与THP-1数据相似，糖尿病患者外周血单核细胞中两个候选基因的编码区和启动子区域的H3K9me2显著高于正常对照组，从而证明了与人类糖尿病的相关性。此外，用cDNA阵列进行的常规mRNA图谱显示了mRNA和H3K9me2水平之间的相关性。这些新的结果首次在全基因组水平上显示了糖尿病条件下组蛋白甲基化的变化。
Aberrant histone lysine methylation patterns that change chromatin structure can promote dysregulated gene transcription and disease progression. Diabetic conditions such as high glucose (HG) are known to alter key pathologic pathways. However, their impact on cellular histone lysine methylation is unknown. We hypothesized that chronic HG can induce aberrant changes in histone H3 lysine 4 and lysine 9 dimethylation (H3K4me2 and H3K9me2) within target cells. Chromatin immunoprecipitation linked to microarrays (ChIP-on-chip) is currently a widely used approach for acquiring genome-wide information on histone modifications. We adopted this approach to profile and compare the variations in H3K4me2 and H3K9me2 in human gene coding and CpG island regions in THP-1 monocytes cultured in normal glucose and HG. Subsequently, we identified key relevant candidate genes displaying differential changes in H3K4me2 and H3K9me2 in HG versus normal glucose and also validated them with follow-up conventional ChIPs. Relevance to human diabetes was demonstrated by noting that H3K9me2 at the coding and promoter regions of two candidate genes was significantly greater in blood monocytes of diabetic patients relative to normal controls similar to the THP-1 data. In addition, regular mRNA profiling with cDNA arrays revealed correlations between mRNA and H3K9me2 levels. These novel results show histone methylation variations, for the first time, under diabetic conditions at a genome-wide level.