Reorganization of chromosome architecture in replicative cellular senescence.
Reorganization of chromosome architecture in replicative cellular senescence.
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DOI：
10.1126/sciadv.1500882
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发表时间：
2016-02
期刊：
影响因子：
13.6
通讯作者：
Neretti N
中科院分区：
文献类型：
--
作者：
Criscione SW;De Cecco M;Siranosian B;Zhang Y;Kreiling JA;Sedivy JM;Neretti N
衰老细胞获得了独特的染色体结构，其特征是染色体臂的全基因组收缩。复制性细胞衰老是一个基本的生物过程，其特征是不可逆的增殖停滞。衰老细胞积累了各种表观遗传变化，但其染色质的三维 (3D) 组织尚不清楚。我们结合使用全基因组染色体构象捕获 (Hi-C)、荧光原位杂交和计算机建模方法来表征增殖、静止和衰老细胞中间期染色体的 3D 结构。尽管染色质整体组织为活性 (A) 和抑制 (B) 区室以及拓扑相关域 (TAD) 在这三种条件下是保守的，但 TAD 的一个子集会在区室之间切换。在整体水平上，衰老细胞的 Hi-C 相互作用矩阵的特征是染色体内长程相互作用的相对损失和短程相互作用的增加。对遗传位点之间的距离、染色体体积和染色质可及性的直接测量表明，Hi-C 相互作用的变化是由单个染色体臂占据的体积显着减少引起的。相反，着丝粒反对这种整体压缩趋势和体积增加。我们的研究产生的结构模型为衰老细胞中复杂的染色体结构提供了独特的高分辨率视图。
Senescent cells acquire a unique chromosome architecture characterized by a genome-wide shrinkage of chromosome arms. Replicative cellular senescence is a fundamental biological process characterized by an irreversible arrest of proliferation. Senescent cells accumulate a variety of epigenetic changes, but the three-dimensional (3D) organization of their chromatin is not known. We applied a combination of whole-genome chromosome conformation capture (Hi-C), fluorescence in situ hybridization, and in silico modeling methods to characterize the 3D architecture of interphase chromosomes in proliferating, quiescent, and senescent cells. Although the overall organization of the chromatin into active (A) and repressive (B) compartments and topologically associated domains (TADs) is conserved between the three conditions, a subset of TADs switches between compartments. On a global level, the Hi-C interaction matrices of senescent cells are characterized by a relative loss of long-range and gain of short-range interactions within chromosomes. Direct measurements of distances between genetic loci, chromosome volumes, and chromatin accessibility suggest that the Hi-C interaction changes are caused by a significant reduction of the volumes occupied by individual chromosome arms. In contrast, centromeres oppose this overall compaction trend and increase in volume. The structural model arising from our study provides a unique high-resolution view of the complex chromosomal architecture in senescent cells.