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Global turnover of histone post-translational modifications and variants in human cells

机译：人类细胞中组蛋白翻译后修饰和变异的全球营业额

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Background Post-translational modifications (PTMs) on the N-terminal tails of histones and histone variants regulate distinct transcriptional states and nuclear events. Whereas the functional effects of specific PTMs are the current subject of intense investigation, most studies characterize histone PTMs/variants in a non-temporal fashion and very few studies have reported kinetic information about these histone forms. Previous studies have used radiolabeling, fluorescence microscopy and chromatin immunoprecipitation to determine rates of histone turnover, and have found interesting correlations between increased turnover and increased gene expression. Therefore, histone turnover is an understudied yet potentially important parameter that may contribute to epigenetic regulation. Understanding turnover in the context of histone modifications and sequence variants could provide valuable additional insight into the function of histone replacement. Results In this study, we measured the metabolic rate of labeled isotope incorporation into the histone proteins of HeLa cells by combining stable isotope labeling of amino acids in cell culture (SILAC) pulse experiments with quantitative mass spectrometry-based proteomics. In general, we found that most core histones have similar turnover rates, with the exception of the H2A variants, which exhibit a wider range of rates, potentially consistent with their epigenetic function. In addition, acetylated histones have a significantly faster turnover compared with general histone protein and methylated histones, although these rates vary considerably, depending on the site and overall degree of methylation. Histones containing transcriptionally active marks have been consistently found to have faster turnover rates than histones containing silent marks. Interestingly, the presence of both active and silent marks on the same peptide resulted in a slower turnover rate than either mark alone on that same peptide. Lastly, we observed little difference in the turnover between nearly all modified forms of the H3.1, H3.2 and H3.3 variants, with the notable exception that H3.2K36me2 has a faster turnover than this mark on the other H3 variants. Conclusions Quantitative proteomics provides complementary insight to previous work aimed at quantitatively measuring histone turnover, and our results suggest that turnover rates are dependent upon site-specific post-translational modifications and sequence variants.
机译：背景组蛋白和组蛋白变体N末端尾部的翻译后修饰（PTM）调节不同的转录状态和核事件。尽管特定PTM的功能作用是当前研究的热点，但大多数研究以非时间方式表征组蛋白PTM /变体，很少有研究报道有关这些组蛋白形式的动力学信息。先前的研究已使用放射性标记，荧光显微镜和染色质免疫沉淀来确定组蛋白更新率，并发现更新率增加和基因表达增加之间有趣的相关性。因此，组蛋白转换是一个尚未被研究但潜在的重要参数，可能有助于表观遗传调控。在组蛋白修饰和序列变异的背景下了解营业额可以为组蛋白替代功能提供有价值的额外见解。结果在这项研究中，我们通过将细胞培养（SILAC）脉冲实验中氨基酸的稳定同位素标记与基于质谱的定量蛋白质组学相结合，测量了掺入HeLa细胞组蛋白的标记同位素的代谢率。通常，我们发现大多数核心组蛋白具有相似的周转率，但H2A变体除外，后者显示出更宽的变化率范围，可能与其表观遗传功能一致。另外，与普通组蛋白和甲基化组蛋白相比，乙酰化组蛋白的周转速度明显加快，尽管这些速率随位点和甲基化程度的不同而有很大差异。一致地发现，含有转录活性标记的组蛋白比含有沉默标记的组蛋白具有更快的周转率。有趣的是，同一肽上同时存在主动标记和沉默标记，导致其周转率比同一肽上单独的任一标记慢。最后，我们观察到H3.1，H3.2和H3.3变体的几乎所有修饰形式之间的转换几乎没有差异，但值得注意的例外是，H3.2K36me2的转换速度比其他H3变体的标记要快。结论定量蛋白质组学为以前的工作提供了补充的见解，旨在定量测量组蛋白的周转率，我们的结果表明周转率取决于位点特异性翻译后修饰和序列变异。

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