Impacts of Chromatin States and Long-Range Genomic Segments on Aging and DNA Methylation.
Impacts of Chromatin States and Long-Range Genomic Segments on Aging and DNA Methylation.
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DOI：
10.1371/journal.pone.0128517
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Yi SV
中科院分区：
文献类型：
--
作者：
Sun D;Yi SV
了解正常衰老过程中表观基因组变异的基本动力学对于阐明影响发育、细胞分化和疾病的关键表观遗传改变至关重要。衰老和DNA甲基化领域的进展有力地支持了衰老表观遗传漂变模型。尽管该模型与先前的研究一致，但其他表观遗传标记的作用，如组蛋白修饰，以及采样特定CpGs的影响，必须进行评估。最终，研究人类基因组中所有CpGs在其特定基因组和表观基因组背景下如何随年龄变化其甲基化是至关重要的。在这里，我们分析了来自不同年龄个体的大脑额叶皮质全基因组亚硫酸氢盐测序DNA甲基化图谱。与血液数据的比较揭示了表观遗传漂变的组织特异性模式。通过整合染色质状态信息，揭示了不同基因组区域衰老相关甲基化的不同程度和方向。亚硫酸氢盐全基因组测序数据也为研究邻近的CpG位点是否随着年龄的增长而表现出协调的DNA甲基化变化打开了新的大门。我们发现了重要的“衰老片段”，这是附近的CpGs集群，它们通过类似的DNA甲基化变化对衰老做出反应。这些片段不仅捕获了先前确定的衰老cpgs，还包括与衰老表观遗传调控相关的特定功能基因类别。例如，与发育相关的基因在阳性衰老片段中高度富集，随着年龄的增长逐渐超甲基化。另一方面，大脑中随着衰老而逐渐低甲基化的区域（“负衰老段”）含有参与代谢和蛋白质泛素化的基因。鉴于蛋白质泛素化在衰老大脑和神经退行性疾病的蛋白质组稳态中的重要性，我们的发现提示了这种翻译后修饰途径在衰老大脑中的表观遗传调控的重要性。利用衰老片段而不是单个CpGs将提供更全面的基因组和表观基因组背景，以了解基因组邻域与发育和衰老过程之间的复杂关联。这些结果补充了衰老表观遗传漂变模型，并提供了新的见解。
Understanding the fundamental dynamics of epigenome variation during normal aging is critical for elucidating key epigenetic alterations that affect development, cell differentiation and diseases. Advances in the field of aging and DNA methylation strongly support the aging epigenetic drift model. Although this model aligns with previous studies, the role of other epigenetic marks, such as histone modification, as well as the impact of sampling specific CpGs, must be evaluated. Ultimately, it is crucial to investigate how all CpGs in the human genome change their methylation with aging in their specific genomic and epigenomic contexts. Here, we analyze whole genome bisulfite sequencing DNA methylation maps of brain frontal cortex from individuals of diverse ages. Comparisons with blood data reveal tissue-specific patterns of epigenetic drift. By integrating chromatin state information, divergent degrees and directions of aging-associated methylation in different genomic regions are revealed. Whole genome bisulfite sequencing data also open a new door to investigate whether adjacent CpG sites exhibit coordinated DNA methylation changes with aging. We identified significant ‘aging-segments’, which are clusters of nearby CpGs that respond to aging by similar DNA methylation changes. These segments not only capture previously identified aging-CpGs but also include specific functional categories of genes with implications on epigenetic regulation of aging. For example, genes associated with development are highly enriched in positive aging segments, which are gradually hyper-methylated with aging. On the other hand, regions that are gradually hypo-methylated with aging (‘negative aging segments’) in the brain harbor genes involved in metabolism and protein ubiquitination. Given the importance of protein ubiquitination in proteome homeostasis of aging brains and neurodegenerative disorders, our finding suggests the significance of epigenetic regulation of this posttranslational modification pathway in the aging brain. Utilizing aging segments rather than individual CpGs will provide more comprehensive genomic and epigenomic contexts to understand the intricate associations between genomic neighborhoods and developmental and aging processes. These results complement the aging epigenetic drift model and provide new insights.
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影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
3.7
作者：
Boks MP;Derks EM;Weisenberger DJ;Strengman E;Janson E;Sommer IE;Kahn RS;Ophoff RA
通讯作者：
Ophoff RA
影响因子：
4.5
作者：
Grönniger E;Weber B;Heil O;Peters N;Stäb F;Wenck H;Korn B;Winnefeld M;Lyko F
通讯作者：
Lyko F
影响因子：
4.5
作者：
Christensen BC;Houseman EA;Marsit CJ;Zheng S;Wrensch MR;Wiemels JL;Nelson HH;Karagas MR;Padbury JF;Bueno R;Sugarbaker DJ;Yeh RF;Wiencke JK;Kelsey KT
通讯作者：
Kelsey KT
影响因子：
3.7
作者：
Bocklandt S;Lin W;Sehl ME;Sánchez FJ;Sinsheimer JS;Horvath S;Vilain E
通讯作者：
Vilain E