A simple biophysical model emulates budding yeast chromosome condensation.
A simple biophysical model emulates budding yeast chromosome condensation.
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DOI：
10.7554/elife.05565
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发表时间：
2015-04-29
期刊：
影响因子：
7.7
通讯作者：
Uhlmann F
中科院分区：
文献类型：
--
作者：
Cheng TM;Heeger S;Chaleil RA;Matthews N;Stewart A;Wright J;Lim C;Bates PA;Uhlmann F
有丝分裂染色体是最早被描述的细胞生物学结构之一，但它们的分子结构仍然知之甚少。我们已经设计了一个简单的生物物理模型的300 kb长的核小体链，大小的一个芽殖酵母染色体，限制染色体凝聚素复合物，间期和有丝分裂染色体的关键组成部分的结合位点之间的相互作用。计算和实验（4C）相互作用的地图，和其他生物物理特征的比较，使我们能够预测的凝聚作用的模式。随机凝聚蛋白介导的成对相互作用沿着核小体链产生天然样的染色体特征，并重演染色体压缩和有丝分裂凝聚过程中的个性化。凝聚素结合位点之间的高阶相互作用解释的数据不太好。我们的研究结果表明，关于染色质行为的基本假设对解释染色体结构有很大帮助，并且能够生成染色体内部可能看起来像什么的分子模型。http://dx.doi.org/10.7554/eLife.05565.001生物的遗传物质是由长链DNA组成的。人类细胞含有大约两米长的DNA，分为46条染色体。这些染色体携带着建造人体的所有指令。为了将所有这些信息都放入每个人类细胞中，DNA包裹着数十万个蛋白质，使得每个染色体都像一串珠子。大多数时候，细胞中的染色体只是松散地排列。但是，当一个细胞准备分裂成两个新细胞时，它的染色体变得更加紧凑。这使得DNA能够承受染色体拷贝被拉入两个子细胞时所涉及的物理力，并且使细胞更容易处理其遗传物质。如果染色体在细胞分裂过程中断裂，就会导致癌症等疾病。有几种蛋白质统称为凝聚蛋白，它们的作用是使染色体紧密（或凝聚）。这些蛋白质存在于许多物种中，但人们对它们如何使染色体变得更紧凑仍知之甚少。由于目前成像方法的技术限制，不可能直接可视化紧凑染色体内DNA链的路径。然而，Cheng等人现在通过结合实验分析和计算模拟克服了这一限制。Cheng等人使用计算机建模来模拟一段染色体，这段染色体的大小与一种叫做芽殖酵母的单细胞微生物的染色体大小相同。这个模型可以精确地重现在非分裂细胞中观察到的染色体行为，并揭示这些染色体处于松弛状态。Cheng等人随后模拟了当引入凝聚素时会发生什么。正如预期的那样，染色体变得更加紧凑，然后使用进一步的实验验证模型的行为。这预示着凝聚素复合物，结合到区域沿着染色体的长度，相互作用，形成对，不断分离，并形成新的对与其他凝聚素;和这些“动态成对”的相互作用紧凑的染色体。目前的模型描述了一个相对较小的染色体，在未来，将该模型扩展到更大的染色体可以提供洞察力。DOI：http://dx.doi.org/10.7554/eLife.05565.002网站
Mitotic chromosomes were one of the first cell biological structures to be described, yet their molecular architecture remains poorly understood. We have devised a simple biophysical model of a 300 kb-long nucleosome chain, the size of a budding yeast chromosome, constrained by interactions between binding sites of the chromosomal condensin complex, a key component of interphase and mitotic chromosomes. Comparisons of computational and experimental (4C) interaction maps, and other biophysical features, allow us to predict a mode of condensin action. Stochastic condensin-mediated pairwise interactions along the nucleosome chain generate native-like chromosome features and recapitulate chromosome compaction and individualization during mitotic condensation. Higher order interactions between condensin binding sites explain the data less well. Our results suggest that basic assumptions about chromatin behavior go a long way to explain chromosome architecture and are able to generate a molecular model of what the inside of a chromosome is likely to look like. DOI: http://dx.doi.org/10.7554/eLife.05565.001 The genetic material of living things is made up of long strands of DNA. Human cells contain about two meters of DNA split between 46 chromosomes. These chromosomes carry all the instructions to build a human body. To fit all of this information inside each human cell, the DNA is wrapped around hundreds of thousands of proteins such that the chromosomes each resemble a string of beads. Most of the time the chromosomes in a cell are only loosely arranged. But, when a cell prepares to divide into two new cells, its chromosomes become more compacted. This allows the DNA to withstand the physical forces involved when the copies of the chromosomes are pulled into the two daughter cells, and it makes it easier for the cell to handle its genetic material. If a chromosome breaks during cell division, it can result in diseases such as cancer. Several proteins—collectively called condensins—work to compact (or condense) the chromosomes. These proteins are found in a wide range of species, but it remains poorly understood how they cause chromosomes to become more compact. Due to the technical limitations of current imaging methods, it has not been possible to directly visualize the path of the DNA strand within a compacted chromosome. However, Cheng et al. have now overcome this limitation by combining experimental analyses and computational simulations. Cheng et al. used computer modeling to simulate a piece of chromosome that was about the same size as a chromosome from a single-celled microorganism called budding yeast. This model could accurately recreate the behavior of chromosomes as observed in non-dividing cells—and revealed that these chromosomes are in a relaxed state. Cheng et al. then modeled what happens when condensins are introduced. As expected, the chromosomes became more compacted and the model's behavior was then validated using further experiments. This predicted that condensin complexes, bound to regions along the chromosome's length, interact to form pairs that continually separate and form new pairs with other condensins; and that these ‘dynamic pairwise’ interactions compact the chromosome. The current model describes a relatively small chromosome and, in the future, extending the model to larger chromosomes could shed insight. DOI: http://dx.doi.org/10.7554/eLife.05565.002