Global reorganization of the nuclear landscape in senescent cells.
Global reorganization of the nuclear landscape in senescent cells.
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DOI：
10.1016/j.celrep.2014.12.055
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发表时间：
2015-02-03
期刊：
影响因子：
8.8
通讯作者：
Reik W
中科院分区：
文献类型：
--
作者：
Chandra T;Ewels PA;Schoenfelder S;Furlan-Magaril M;Wingett SW;Kirschner K;Thuret JY;Andrews S;Fraser P;Reik W
细胞衰老与肿瘤抑制、发育和衰老有关，并伴随着大规模的染色质重排，形成衰老相关异染色质灶（SAHF）。然而，在SAHF形成过程中染色质是如何重组的还知之甚少。此外，异染色质的形成在衰老似乎与异染色质的损失在Hutchinson-Gilford早衰症形成对比。我们使用Hi-C绘制了细胞衰老中基因组组织的结构变化。出乎意料的是，我们发现了一个戏剧性的序列和层粘连蛋白依赖性的损失，在异染色质的局部相互作用。这种局部连接的变化解决了衰老和早衰中染色质变化的矛盾。此外，我们观察到异染色质区域的衰老特异性空间聚类，这表明SAHF形成所需的独特的第二步。比较胚胎干细胞（ESC），体细胞和衰老细胞显示局部染色质连接的单向损失，表明衰老是分化过程中连续核重塑过程的终点。SAHF细胞显示异染色质（HC）结构的序列和LAD依赖性损失衰老HC行为反映在Hutchinson-Gilford早衰症中HC的衰老特异性空间聚类导致SAHF形成的新模型比较ESC，体细胞和衰老细胞将衰老与分化联系起来。使用Hi-C绘制细胞衰老中基因组组织的变化。相反，相信在异染色质增加衰老相关的异染色质病灶的形成，他们描述了一个损失的异染色质区域的局部相互作用。这与在早衰细胞中观察到的变化一致。
Cellular senescence has been implicated in tumor suppression, development, and aging and is accompanied by large-scale chromatin rearrangements, forming senescence-associated heterochromatic foci (SAHF). However, how the chromatin is reorganized during SAHF formation is poorly understood. Furthermore, heterochromatin formation in senescence appears to contrast with loss of heterochromatin in Hutchinson-Gilford progeria. We mapped architectural changes in genome organization in cellular senescence using Hi-C. Unexpectedly, we find a dramatic sequence- and lamin-dependent loss of local interactions in heterochromatin. This change in local connectivity resolves the paradox of opposing chromatin changes in senescence and progeria. In addition, we observe a senescence-specific spatial clustering of heterochromatic regions, suggesting a unique second step required for SAHF formation. Comparison of embryonic stem cells (ESCs), somatic cells, and senescent cells shows a unidirectional loss in local chromatin connectivity, suggesting that senescence is an endpoint of the continuous nuclear remodelling process during differentiation. SAHF cells show sequence- and LAD-dependent loss of heterochromatin (HC) structure Senescence HC behavior is mirrored in Hutchinson-Gilford progeria Senescence-specific spatial clustering of HC leads to a new model for SAHF formation Comparing ESCs, somatic, and senescent cells links senescence to differentiation Chandra, Ewels, et al. map changes in genome organization in cellular senescence using Hi-C. Contrary to the believed increase in heterochromatin in senescence-associated heterochromatic foci formation, they describe a loss of local interactions in heterochromatic regions. This is in agreement with changes observed in progeria cells.