Histone code modifications on pluripotential nuclei of reprogrammed somatic cells
Histone code modifications on pluripotential nuclei of reprogrammed somatic cells
复制标题
DOI：
10.1128/mcb.24.13.5710-5720.2004
复制
发表时间：
2004-07-01
影响因子：
5.3
通讯作者：
Tada, T
中科院分区：
文献类型：
--
作者：
Kimura, H;Tada, M;Tada, T
在与胚胎干细胞(ES)杂交后，体细胞基因组被表观遗传重新编程并获得多能性。这导致了分化时体细胞基因组衍生的组织特异性基因的转录。在核重新编程期间，被认为在细胞类型特异性表观类型记忆中起作用的DNA和染色质修饰应该被显著修改。事实上，目前的证据表明，组蛋白H3和H4氨基末端的乙酰化和甲基化在通过调节染色质构象来调节基因活性方面发挥了重要作用。在这里，我们发现ES杂交细胞的重新编程的体细胞基因组在H3和H4变得超乙酰化，而H3的赖氨酸4(K4)变得全局超二甲基化和三甲基化。在Oct4启动子区域，组蛋白H3和H4被乙酰化，H3-K4在ES和重新编程的体细胞基因组上高度三甲基化，这与基因激活和DNA去甲基化有关。然而，H3-K4在神经细丝-M(NFM)、NFL和Thy-1的启动子区域也有二甲基化和三甲基化，这些启动子在ES细胞和杂交细胞中都是沉默的。因此，重新编程的体细胞基因组的H3-K4二和三甲基化独立于基因活性，并代表了在体细胞基因组重新编程过程中发生的主要事件之一，使其进入转录激活-允许状态。
Following hybridization with embryonic stem (ES) cells, somatic genomes are epigenetically reprogrammed and acquire pluripotency. This results in the transcription of somatic genome-derived tissue-specific genes upon differentiation. During nuclear reprogramming, it is expected that DNA and chromatin modifications, believed to function in cell-type-specific epigenotype memory, should be significantly modified. Indeed, current evidence indicates that acetylation and methylation of histone H3 and H4 amino termini play a major role in the regulation of gene activity through the modulation of chromatin conformation. Here, we show that the reprogrammed somatic genome of ES hybrid cells becomes hyperacetylated at H3 and H4, while lysine 4 (K4) of H3 becomes globally hyper-di- and -tri-methylated. In the Oct4 promoter region, histones H3 and H4 are acetylated and H3-K4 is highly tri-methylated on both the ES and reprogrammed somatic genomes, which correlates with gene activation and DNA demethylation. However, H3-K4 is also di- and tri-methylated in the promoter regions of Neurofilament-M (Nfm), Nfl, and Thy-1, which are all silent in both ES and hybrid cells. Thus, H3-K4 di- and tri-methylation of reprogrammed somatic genomes is independent of gene activity and represents one of the major events that occurs during somatic genome reprogramming towards a transcriptional activation-permissive state.