H4K20 methylation regulates quiescence and chromatin compaction.
H4K20 methylation regulates quiescence and chromatin compaction.
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DOI：
10.1091/mbc.e12-07-0529
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发表时间：
2013-10
影响因子：
3.3
通讯作者：
Coller HA
中科院分区：
文献类型：
--
作者：
Evertts AG;Manning AL;Wang X;Dyson NJ;Garcia BA;Coller HA
K20在组蛋白H4上的甲基化状态对于人成纤维细胞中适当的细胞周期控制和染色质紧凑是重要的。高水平的二甲基化和三甲基化的K20与静止有关，这些修饰的丢失会导致染色质构象更加开放，并导致细胞周期进程和退出的缺陷。细胞增殖和静止之间的转换通常与基因表达的变化、染色质致密程度和组蛋白修饰有关，但染色质状态的变化是否真的调节细胞周期静止退出尚不清楚。我们发现，被诱导进入静止状态的原代人成纤维细胞显示出更紧密的染色质紧致。组蛋白修饰的质谱分析显示，H4K20me2和H4K20me3在静止期增加，其他组蛋白修饰在增殖和静止期细胞中存在相似的水平。对S期、G2/M期和G1期细胞的分析表明，H4K20me1在S期后增加，并在静止时转化为H4K20me2和H4K20me3。抑制产生H4K20me3的酶会导致处于S期的细胞比例增加，退出细胞周期的缺陷，染色质致密性降低。Suv4-20h1是从H4K20me1产生H4K20me2的酶，过表达会导致G2期停滞，这与H4K20me1在有丝分裂中的作用一致。结果表明，H4K20上的同一赖氨酸在不同的甲基化状态下，可能促进了M期的有丝分裂功能，并促进了静止细胞的染色质压缩和细胞周期退出。
The methylation state of K20 on histone H4 is important for proper cell cycle control and chromatin compaction in human fibroblasts. High levels of dimethylated and trimethylated K20 are associated with quiescence, and loss of these modifications causes a more open chromatin conformation and defects in cell cycle progression and exit. The transition between proliferation and quiescence is frequently associated with changes in gene expression, extent of chromatin compaction, and histone modifications, but whether changes in chromatin state actually regulate cell cycle exit with quiescence is unclear. We find that primary human fibroblasts induced into quiescence exhibit tighter chromatin compaction. Mass spectrometry analysis of histone modifications reveals that H4K20me2 and H4K20me3 increase in quiescence and other histone modifications are present at similar levels in proliferating and quiescent cells. Analysis of cells in S, G2/M, and G1 phases shows that H4K20me1 increases after S phase and is converted to H4K20me2 and H4K20me3 in quiescence. Knockdown of the enzyme that creates H4K20me3 results in an increased fraction of cells in S phase, a defect in exiting the cell cycle, and decreased chromatin compaction. Overexpression of Suv4-20h1, the enzyme that creates H4K20me2 from H4K20me1, results in G2 arrest, consistent with a role for H4K20me1 in mitosis. The results suggest that the same lysine on H4K20 may, in its different methylation states, facilitate mitotic functions in M phase and promote chromatin compaction and cell cycle exit in quiescent cells.