Replicative senescence is associated with nuclear reorganization and with DNA methylation at specific transcription factor binding sites.
Replicative senescence is associated with nuclear reorganization and with DNA methylation at specific transcription factor binding sites.
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复制性衰老与特定转录因子结合位点处的核重组和DNA甲基化有关。
DOI：
10.1186/s13148-015-0057-5
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发表时间：
2015
影响因子：
5.7
通讯作者：
Wagner W
中科院分区：
文献类型：
--
作者：
Hänzelmann S;Beier F;Gusmao EG;Koch CM;Hummel S;Charapitsa I;Joussen S;Benes V;Brümmendorf TH;Reid G;Costa IG;Wagner W
原代细胞在有限数量的细胞分裂后进入复制衰老。这一过程需要在细胞培养实验中考虑，对再生医学来说尤为重要。复制性衰老与基因组中特定位置的DNA甲基化(DNaM)的可复制变化有关。驱动衰老相关dNaM变化的机制尚不清楚-它可能涉及由于不完善的表观遗传标记维护而导致的随机dNaM漂移，或者它直接在基因组的特定位置受到调控。在这项研究中，我们分析了人成纤维细胞和间充质基质细胞(MSCs)在长期培养过程中核结构的重组和dNaM的变化。我们证明了端粒缩短，并在以后的传代中向核中心移动。此外，通过甲基帽序列或450k IlllightaBeadChip技术分析的dNaM图谱显示，在与H3K27me3、H3K4me3和H3K4me1组蛋白标记相关的区域中，与衰老相关的高甲基化一致，而低甲基化与含有H3K9me3和层相关结构域(LADS)的染色质相关。DNA高甲基化显著地丰富在基因附近，这些基因在以后的传代中要么上调，要么下调。此外，特异性转录因子结合基序(如Egr1、TFAP2A和ETS1)在差异甲基化区域和差异表达基因的启动子中显著丰富。衰老相关的DNA高甲基化发生在基因组的特定位置，反映了复制性衰老过程中的功能变化。这些结果表明，长期培养过程中严格调控的表观遗传修饰有助于核组织和基因表达的变化。本文的在线版本(doi：10.1186/s13148-0150057-5)包含补充材料，授权用户可以使用。
Primary cells enter replicative senescence after a limited number of cell divisions. This process needs to be considered in cell culture experiments, and it is particularly important for regenerative medicine. Replicative senescence is associated with reproducible changes in DNA methylation (DNAm) at specific sites in the genome. The mechanism that drives senescence-associated DNAm changes remains unknown - it may involve stochastic DNAm drift due to imperfect maintenance of epigenetic marks or it is directly regulated at specific sites in the genome. In this study, we analyzed the reorganization of nuclear architecture and DNAm changes during long-term culture of human fibroblasts and mesenchymal stromal cells (MSCs). We demonstrate that telomeres shorten and shift towards the nuclear center at later passages. In addition, DNAm profiles, either analyzed by MethylCap-seq or by 450k IlluminaBeadChip technology, revealed consistent senescence-associated hypermethylation in regions associated with H3K27me3, H3K4me3, and H3K4me1 histone marks, whereas hypomethylation was associated with chromatin containing H3K9me3 and lamina-associated domains (LADs). DNA hypermethylation was significantly enriched in the vicinity of genes that are either up- or downregulated at later passages. Furthermore, specific transcription factor binding motifs (e.g. EGR1, TFAP2A, and ETS1) were significantly enriched in differentially methylated regions and in the promoters of differentially expressed genes. Senescence-associated DNA hypermethylation occurs at specific sites in the genome and reflects functional changes in the course of replicative senescence. These results indicate that tightly regulated epigenetic modifications during long-term culture contribute to changes in nuclear organization and gene expression. The online version of this article (doi:10.1186/s13148-015-0057-5) contains supplementary material, which is available to authorized users.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
全基因组甲基化谱揭示了人类衰老速度的定量观点。
影响因子：
16
作者：
Hannum, Gregory;Guinney, Justin;Zhao, Ling;Zhang, Li;Hughes, Guy;Sadda, SriniVas;Klotzle, Brandy;Bibikova, Marina;Fan, Jian-Bing;Gao, Yuan;Deconde, Rob;Chen, Menzies;Rajapakse, Indika;Friend, Stephen;Ideker, Trey;Zhang, Kang
通讯作者：
Zhang, Kang
影响因子：
3.3
作者：
Freund A;Laberge RM;Demaria M;Campisi J
通讯作者：
Campisi J
影响因子：
7.5
作者：
Cremer, Thomas;Cremer, Marion;Fakan, Stanislav
通讯作者：
Fakan, Stanislav
影响因子：
11.4
作者：
Gonzalez-Suarez, Ignacio;Redwood, Abena B.;Gonzalo, Susana
通讯作者：
Gonzalo, Susana