Deciphering the molecular mechanism of the cancer formation by chromosome structural dynamics.
Deciphering the molecular mechanism of the cancer formation by chromosome structural dynamics.
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DOI：
10.1371/journal.pcbi.1009596
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发表时间：
2021-11
影响因子：
4.3
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Chu X;Wang J
癌症反映了潜在基因网络的失调，这与3D基因组组织密切相关。许多努力已经花费在癌症基因组结构改变的实验表征上。然而，仍然缺乏对癌症发生和进展的时间动态的基因组结构水平的理解。在这里，我们使用一个交换模型来研究在癌变和逆转过程中染色体结构的转变。我们发现，在这两个过程中，染色体经历了一个非单调的结构形状变化的途径与最初的扩张，然后压实。此外，我们的分析表明，在癌变过程中，染色体具有比正常细胞和癌细胞更膨胀的结构，表现出稀疏的接触模式，这在许多方面显示出与胚胎干细胞的结构相似性，包括接触概率随基因组距离下降的趋势，整体结构形状几何形状和染色体上位点的空间分布。鉴于在染色体水平上密切的结构-功能关系，我们进一步描述了细胞状态的转变过程中的染色体结构的变化，表明在癌细胞的形成过程中，细胞的干细胞性升高。我们表明，细胞癌变和逆转是高度不可逆的过程中的染色体结构转换途径，染色体位点的空间重新定位和接触进化分析的滞后环。我们的模型从染色体结构的角度绘制了细胞癌变的分子尺度图像。该过程包含向干细胞的初始重编程，然后向癌细胞分化，伴随着细胞干细胞性的初始增加和随后的减少。癌症是人类死亡的主要原因之一。癌症是由基因表达的潜在调控网络调控的，这些基因表达与3D染色体结构密切相关。许多努力已经花费在阐明肿瘤发生中的染色体结构变异上，而在癌症形成期间染色体结构如何演变的动态图像仍然缺失。在这里，我们将Hi-C数据整合到聚合物模拟中，以构建正常和癌细胞中的染色体结构集合。然后，我们使用一个非平衡态的染色体开关模型来模拟癌变和逆转过程中的染色体结构动力学。与量化的途径，我们表明，在癌症形成的短暂中间状态的染色体具有显着程度的结构相似性的干细胞。我们的研究结果表明，从染色体结构的角度来看，在癌症形成过程中形成了干细胞样状态。我们绘制了癌症形成的分子尺度图像，其中包含向干细胞的初始重编程，然后向癌细胞分化。
Cancer reflects the dysregulation of the underlying gene network, which is strongly related to the 3D genome organization. Numerous efforts have been spent on experimental characterizations of the structural alterations in cancer genomes. However, there is still a lack of genomic structural-level understanding of the temporal dynamics for cancer initiation and progression. Here, we use a landscape-switching model to investigate the chromosome structural transition during the cancerization and reversion processes. We find that the chromosome undergoes a non-monotonic structural shape-changing pathway with initial expansion followed by compaction during both of these processes. Furthermore, our analysis reveals that the chromosome with a more expanding structure than those at both the normal and cancer cell during cancerization exhibits a sparse contact pattern, which shows significant structural similarity to the one at the embryonic stem cell in many aspects, including the trend of contact probability declining with the genomic distance, the global structural shape geometry and the spatial distribution of loci on the chromosome. In light of the intimate structure-function relationship at the chromosomal level, we further describe the cell state transition processes by the chromosome structural changes, suggesting an elevated cell stemness during the formation of the cancer cells. We show that cell cancerization and reversion are highly irreversible processes in terms of the chromosome structural transition pathways, spatial repositioning of chromosomal loci and hysteresis loop of contact evolution analysis. Our model draws a molecular-scale picture of cell cancerization from the chromosome structural perspective. The process contains initial reprogramming towards the stem cell followed by the differentiation towards the cancer cell, accompanied by an initial increase and subsequent decrease of the cell stemness. Cancer is among the leading causes of human death. Cancer is regulated by the underlying regulatory network of gene expressions, which are in intimate relation to the 3D chromosome architectures. Numerous efforts have been spent on elucidating the chromosome structural variants in tumorigenesis, while the dynamical picture of how chromosomes structurally evolve during cancer formation is still missing. Here we integrate the Hi-C data into the polymer simulations to build the chromosome structural ensembles in the normal and cancer cells. Then we use a nonequilibrium landscape-switching model to simulate the chromosome structural dynamics during the cancerization and reversion processes. With quantified pathways, we show that the chromosomes at transient intermediate states in the cancer formation possess a significant degree of structural similarity to those at the stem cell. Our findings indicate the formation of stem-like states during cancer formation from the chromosome structural perspective. We draw a molecular-scale picture of the cancer formation, which contains initial reprogramming towards the stem cell followed by differentiation towards the cancer cell.
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影响因子：
4.6
作者：
Ashwin SS;Sasai M
通讯作者：
Sasai M
影响因子：
30.8
作者：
Akdemir, Kadir C.;Le, Victoria T.;Zhang, Cheng-Zhong
通讯作者：
Zhang, Cheng-Zhong
影响因子：
78.5
作者：
Bjerkvig, R;Tysnes, BB;Terzis, AJA
通讯作者：
Terzis, AJA
DOI：
10.1126/science.aau1783
发表时间：
2018-10-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bintu B;Mateo LJ;Su JH;Sinnott-Armstrong NA;Parker M;Kinrot S;Yamaya K;Boettiger AN;Zhuang X
通讯作者：
Zhuang X
影响因子：
30.8
作者：
Akdemir KC;Le VT;Kim JM;Killcoyne S;King DA;Lin YP;Tian Y;Inoue A;Amin SB;Robinson FS;Nimmakayalu M;Herrera RE;Lynn EJ;Chan K;Seth S;Klimczak LJ;Gerstung M;Gordenin DA;O'Brien J;Li L;Deribe YL;Verhaak RG;Campbell PJ;Fitzgerald R;Morrison AJ;Dixon JR;Andrew Futreal P
通讯作者：
Andrew Futreal P