Unique patterns of trimethylation of histone H3 lysine 4 are prone to changes during aging in Caenorhabditis elegans somatic cells.
Unique patterns of trimethylation of histone H3 lysine 4 are prone to changes during aging in Caenorhabditis elegans somatic cells.
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DOI：
10.1371/journal.pgen.1007466
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发表时间：
2018-06
期刊：
影响因子：
4.5
通讯作者：
Lee SS
中科院分区：
文献类型：
--
作者：
Pu M;Wang M;Wang W;Velayudhan SS;Lee SS
组蛋白H3赖氨酸4 （H3K4me3）上的三甲基化与活跃的基因表达有关，但其在转录激活中的调节作用尚不清楚。本研究以秀丽隐杆线虫为研究对象，研究衰老过程中H3K4me3与基因表达调控的关系。我们发现了大约30%的H3K4me3富集区域，显示出随年龄的显著和可重复的变化。我们进一步表明，这些年龄动态的H3K4me3区域主要标记基因体，并在成年阶段获得。我们发现这些成人特异性年龄动态H3K4me3区域与基因表达随年龄变化相关。相比之下，在发育阶段建立的H3K4me3标记随着年龄的增长基本保持稳定，即使H3K4me3相关基因在衰老过程中表现出RNA表达的变化。重要的是，与H3K4me3和RNA水平随年龄变化相关的基因在与衰老生物学相关的功能群中富集。因此，我们的研究结果提示H3K4me3在衰老过程中基因表达调控中的不同作用，对衰老依赖的病理生理具有重要意义。组蛋白修饰是对组蛋白进行的特异性化学修饰，是调控DNA包装的关键，对多种生物过程具有重要影响。组蛋白修饰的一个被广泛研究的功能是它们对调节基因表达的贡献。最近对多种模式生物的研究表明，特定组蛋白修饰的整体改变，例如H3K4me3，可以延长生物体的寿命。然而，潜在的分子机制在很大程度上仍不清楚。在这项研究中，我们监测了模式生物秀丽隐杆线虫体细胞中组蛋白修饰H3K4me3的全基因组模式是否以及如何在衰老过程中发生变化。我们发现了有趣的和非传统的H3K4me3模式，这些模式跨越基因体，在成年期获得，特别容易随着年龄的增长而改变。这与经过充分研究的H3K4me3模式形成对比，H3K4me3模式跨越转录起始位点和5 '启动子区域，在发育早期建立，随着年龄的增长保持稳定。与H3K4me3标记与活性转录之间的密切联系一致，我们观察到年龄动态H3K4me3标记与相应的RNA表达变化高度相关。重要的是，与H3K4me3和RNA表达随年龄变化相关的基因在与衰老生物学相关的功能群中被过度代表。总之，我们的研究结果揭示了一种鲜为人知的H3K4me3修饰模式，该模式在衰老中可能具有重要的生物学作用。
Tri-methylation on histone H3 lysine 4 (H3K4me3) is associated with active gene expression but its regulatory role in transcriptional activation is unclear. Here we used Caenorhabditis elegans to investigate the connection between H3K4me3 and gene expression regulation during aging. We uncovered around 30% of H3K4me3 enriched regions to show significant and reproducible changes with age. We further showed that these age-dynamic H3K4me3 regions largely mark gene-bodies and are acquired during adult stages. We found that these adult-specific age-dynamic H3K4me3 regions are correlated with gene expression changes with age. In contrast, H3K4me3 marking established during developmental stages remained largely stable with age, even when the H3K4me3 associated genes exhibited RNA expression changes during aging. Importantly, the genes associated with changes in H3K4me3 and RNA levels with age are enriched for functional groups commonly implicated in aging biology. Therefore, our findings suggested divergent roles of H3K4me3 in gene expression regulation during aging, with important implications on aging-dependent pathophysiologies. Histone modifications, the specific chemical modifications on histone proteins, are key for regulating the packing of DNA, and thus have important influence on diverse biological processes. An intensely studied function of histone modifications is their contribution to regulating gene expression. Recent studies in diverse model organisms demonstrated that the global alterations of particular histone modifications, for instance H3K4me3, extend the lifespan of the organism. However, the underlying molecular mechanisms remain largely unclear. In this study, we monitored whether and how the genome-wide pattern of the histone modification H3K4me3 changes during aging in the somatic cells of the model organism C. elegans. We identified interesting and non-conventional patterns of H3K4me3, which span gene-bodies and are acquired during adulthood, that are particularly prone to changes with aging. This is contrasted to the well-studied H3K4me3 patterns that span transcriptional start sites and 5’ promoter regions and are established early during development, which remain stable with age. Consistent with the close association between H3K4me3 marking and active transcription, we observed that the age-dynamic H3K4me3 markings are highly correlated with corresponding RNA expression changes. Importantly, the genes that are associated with both H3K4me3 and RNA expression changes with age are over-represented for functional groups commonly implicated in aging biology. In summary, our findings revealed a lesser known pattern of H3K4me3 modification that can have important biological roles in aging.
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