Region-specific H3K9me3 gain in aged somatic tissues in Caenorhabditis elegans.
Region-specific H3K9me3 gain in aged somatic tissues in Caenorhabditis elegans.
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秀丽隐杆线虫衰老体组织中区域特异性H3K9me3的获得
DOI：
10.1371/journal.pgen.1009432
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发表时间：
2021-09
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：
Li CL;Pu M;Wang W;Chaturbedi A;Emerson FJ;Lee SS
表观遗传改变随着生物体年龄的增长而发生，并导致染色质退化、转录沉默丧失和基因组不稳定。表观基因组的失调与年龄相关疾病的易感性增加有关。在这项研究中，我们旨在表征表观基因组的年龄依赖性变化，进而了解驱动衰老表型的表观遗传过程。我们关注秀丽隐杆线虫中抑制组蛋白标记H3K9me3和H3K27me3的衰老相关变化。我们观察到两种组蛋白标记的区域特异性增加和减少，但H3K9me3的变化更为明显。我们进一步发现在衰老的体细胞组织中异色边界发生了改变。有趣的是，我们发现统计上最显著的变化反映了在衰老过程中形成的h3k9me3标记区域，并且在发育中的蠕虫中不存在，我们称之为“衰老特异性抑制区域”（asrr）。这些asrr优先发生在幼虫期以H3K9me2和H3K36me2高水平标记的基因区域。在这些区域维持高水平的H3K9me2已被证明与更长的寿命相关。接下来，我们研究了抑制性组蛋白标记的变化是否会导致重复DNA元件的去沉默，正如在其他几种生物体中报道的那样。我们观察到活跃的重复DNA元件的表达增加，但沉默的重复片段在老蠕虫中没有全局重新激活，可能是由于线虫基因组中重复元件的分布性质。有趣的是，CELE45，一种假定的短分散核元素（sin），在老年和热应激时被过度表达。在哺乳动物中，已经有人提出在各种细胞应激下调节转录。CELE45 rna可能也在秀丽隐杆线虫的应激反应和衰老中发挥作用。综上所述，我们的研究揭示了抑制性组蛋白修饰和重复元件的显著和特定的年龄依赖性变化，为衰老生物学提供了重要的见解。异染色质是指基因组中紧密堆积的部分，基因在那里保持沉默。异染色质通常被称为组蛋白修饰的特殊化学基团修饰，例如组蛋白3上赖氨酸9或赖氨酸27的三甲基化（H3K9me3或H3K27me3）。为了了解异染色质景观如何从“年轻”状态转变为“衰老”状态，我们使用遗传模型土壤线虫监测了H3K9me3和H3K27me3在衰老过程中的全基因组模式。我们发现，虽然H3K27me3随着年龄的增长保持相对稳定，但H3K9me3在老龄蠕虫的特定位点上表现出明显的增减。我们观察到，新的h3k9me3标记的异染色质优先在老龄蠕虫的特定基因丰富区域形成。有趣的是，这些特定的区域在蠕虫年轻时被另外三种高水平的组蛋白修饰所标记。这一结果表明，H3K9me3在衰老过程中的获得受到年轻时建立的组蛋白修饰的基因特异性景观的影响，而不是以随机方式发生。总之，我们的研究发现了组蛋白修饰中可重复的和基因特异性的变化，这些变化可能导致衰老表型。
Epigenetic alterations occur as organisms age, and lead to chromatin deterioration, loss of transcriptional silencing and genomic instability. Dysregulation of the epigenome has been associated with increased susceptibility to age-related disorders. In this study, we aimed to characterize the age-dependent changes of the epigenome and, in turn, to understand epigenetic processes that drive aging phenotypes. We focused on the aging-associated changes in the repressive histone marks H3K9me3 and H3K27me3 in C. elegans. We observed region-specific gain and loss of both histone marks, but the changes are more evident for H3K9me3. We further found alteration of heterochromatic boundaries in aged somatic tissues. Interestingly, we discovered that the most statistically significant changes reflected H3K9me3-marked regions that are formed during aging, and are absent in developing worms, which we termed “aging-specific repressive regions” (ASRRs). These ASRRs preferentially occur in genic regions that are marked by high levels of H3K9me2 and H3K36me2 in larval stages. Maintenance of high H3K9me2 levels in these regions have been shown to correlate with a longer lifespan. Next, we examined whether the changes in repressive histone marks lead to de-silencing of repetitive DNA elements, as reported for several other organisms. We observed increased expression of active repetitive DNA elements but not global re-activation of silent repeats in old worms, likely due to the distributed nature of repetitive elements in the C. elegans genome. Intriguingly, CELE45, a putative short interspersed nuclear element (SINE), was greatly overexpressed at old age and upon heat stress. SINEs have been suggested to regulate transcription in response to various cellular stresses in mammals. It is likely that CELE45 RNAs also play roles in stress response and aging in C. elegans. Taken together, our study revealed significant and specific age-dependent changes in repressive histone modifications and repetitive elements, providing important insights into aging biology. Heterochromatin refers to the portion of the genome that is tightly packed where genes stay silent. Heterochromatin is typically decorated by particular chemical groups called histone modifications, such as trimethylation of lysine 9 or lysine 27 on histone 3 (H3K9me3 or H3K27me3). To understand how the heterochromatin landscape may change from a "youthful" to an "aged" state, we monitored the genome-wide patterns of H3K9me3 and H3K27me3 during aging using the genetic model soil worm C. elegans. We found that while H3K27me3 remained relatively stable with age, H3K9me3 showed substantial gain and loss at specific loci in aged worms. We observed that new H3K9me3-marked heterochromatin preferentially formed in specific gene-rich regions in aged worms. Interestingly, these particular regions were marked by high levels of three other histone modifications when worms were young. This result suggested that H3K9me3 gain during aging is influenced by the gene-specific landscape of histone modifications established at young age rather than that it occurs in a stochastic manner. In summary, our study discovered reproducible and gene-specific changes in histone modifications that likely contribute to the aging phenotypes.
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DOI：
10.1038/s41576-020-0245-9
发表时间：
2020-09
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
Chen Z;Zhang Y
通讯作者：
Zhang Y
影响因子：
7.8
作者：
Chen H;Zheng X;Xiao D;Zheng Y
通讯作者：
Zheng Y
DOI：
10.1093/bioinformatics/btv562
发表时间：
2016-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Gel B;Díez-Villanueva A;Serra E;Buschbeck M;Peinado MA;Malinverni R
通讯作者：
Malinverni R
影响因子：
64.8
作者：
Cabianca, Daphne S.;Munoz-Jimenez, Celia;Gasser, Susan M.
通讯作者：
Gasser, Susan M.
影响因子：
6.7
作者：
Dennis, Shannon;Sheth, Ujwal;Priess, James R.
通讯作者：
Priess, James R.