Computational and genetic reduction of a cell cycle to its simplest, primordial components.
Computational and genetic reduction of a cell cycle to its simplest, primordial components.
复制标题
DOI：
10.1371/journal.pbio.1001749
复制
发表时间：
2013-12
期刊：
影响因子：
9.8
通讯作者：
Howard M
中科院分区：
文献类型：
--
作者：
Murray SM;Panis G;Fumeaux C;Viollier PH;Howard M
在细菌Caulobacter crescentus中的数学建模和遗传学通过关键转录因子GcrA和甲基转移酶CcrM的可分配性确定了不对称细胞周期调节中的冗余，它们一起形成遗传模块。维持不对称细胞周期的最低要求是什么？在这里，我们使用数学建模和正向遗传学将不对称细胞周期减少到最简单的原始组成部分。在α变形杆菌Caulobacter crescentus中，细胞周期进程被认为是由包括四个基本主调节因子的周期性遗传回路控制的。出乎意料的是，我们的计算机模拟预测，这些监管机构之一，GcrA，实际上是不稳定的。我们通过实验证实了这一点，发现ΔgcrA细胞是可行的，但生长缓慢且伸长，后者主要是由于关键细胞分裂蛋白不足。此外，抑制因子分析显示，另一种细胞周期调节因子甲基转移酶CcrM类似地与同时的gcrA/ccrM破坏一起被抑制，从而改善ΔgcrA细胞的细胞动力学和生长缺陷。在Alphaproteobacteria中，gcrA和ccrM是一致存在或不存在的，而不是单独存在的基因，这表明gcrA/ccrM构成了一个独立的，共同的遗传模块。我们的方法共同揭示了原始不对称细胞周期的基本要素，这将有助于阐明更复杂的细胞周期。细胞周期调控非常复杂，即使在简单的细胞中，基本原理也很难理解。新月柄杆菌是研究细胞周期调节的流行模式生物，其归因于由细胞分裂产生的两种不同的子细胞：移动的“群集”细胞和粘附于表面的“柄状”细胞。在这里，我们使用数学建模和遗传实验来确定这些细菌的不对称细胞周期的核心组成部分。使用我们的数学模型，我们预测和实验证实，转录因子和细胞周期调节因子，GcrA，迄今为止被认为是必不可少的，实际上是不稳定的。我们还确定了另一个主要的调节因子，甲基转移酶，CcrM作为甲基转移酶。此外，GcrA和CcrM两者的同时缺失消除了在任一单一缺失上观察到的严重细胞分裂缺陷，使细胞恢复到接近野生型形态。我们发现，GcrA和CcrM构成了一个独立的，可移植的，遗传模块，调节转录的细胞动力学蛋白在细胞周期。系统发育，该模块是保守的Alphaproteobacteria，柄杆菌类，但不存在于树根的类，这表明我们已经确定了原始核心的不对称细胞周期调控电路的Alphaproteobacteria。
Mathematical modelling and genetics in the bacterium Caulobacter crescentus identified redundancy in asymmetric cell cycle regulation through the dispensability of key transcription factor GcrA and methyltransferase CcrM, which together form a genetic module. What are the minimal requirements to sustain an asymmetric cell cycle? Here we use mathematical modelling and forward genetics to reduce an asymmetric cell cycle to its simplest, primordial components. In the Alphaproteobacterium Caulobacter crescentus, cell cycle progression is believed to be controlled by a cyclical genetic circuit comprising four essential master regulators. Unexpectedly, our in silico modelling predicted that one of these regulators, GcrA, is in fact dispensable. We confirmed this experimentally, finding that ΔgcrA cells are viable, but slow-growing and elongated, with the latter mostly due to an insufficiency of a key cell division protein. Furthermore, suppressor analysis showed that another cell cycle regulator, the methyltransferase CcrM, is similarly dispensable with simultaneous gcrA/ccrM disruption ameliorating the cytokinetic and growth defect of ΔgcrA cells. Within the Alphaproteobacteria, gcrA and ccrM are consistently present or absent together, rather than either gene being present alone, suggesting that gcrA/ccrM constitutes an independent, dispensable genetic module. Together our approaches unveil the essential elements of a primordial asymmetric cell cycle that should help illuminate more complex cell cycles. Cell cycle regulation is remarkably complex and the fundamental principles difficult to understand, even in simple cells. The bacterium Caulobacter crescentus is a popular model organism to study cell cycle regulation due to the two different daughter cells resulting from cell division: a mobile “swarmer” cell and a “stalked” cell that adheres to surfaces. Here, we use mathematical modelling and genetic experiments to identify the core components of the asymmetric cell cycle of these bacteria. Using our mathematical model we predicted and confirmed experimentally that the transcription factor and cell cycle regulator, GcrA, hitherto thought to be essential, is in fact dispensable. We also identified another master regulator, the methyltransferase, CcrM as dispensable. Furthermore, simultaneous deletion of both GcrA and CcrM removes the severe cell division defects observed on either single deletion, returning cells to near wild-type morphology. We found that GcrA and CcrM constitute an independent, dispensable, genetic module that regulates transcription of cytokinetic proteins during the cell cycle. Phylogenetically, the module is conserved in Alphaproteobacteria, the class of Caulobacter, but is not present in the tree root of the class, suggesting that we have identified the primordial core of the asymmetric cell cycle regulatory circuit in the Alphaproteobacteria.
登录
查看更多内容
影响因子：
4.5
作者：
Fioravanti A;Fumeaux C;Mohapatra SS;Bompard C;Brilli M;Frandi A;Castric V;Villeret V;Viollier PH;Biondi EG
通讯作者：
Biondi EG
影响因子：
64.5
作者：
Domian, IJ;Quon, KC;Shapiro, L
通讯作者：
Shapiro, L
DOI：
10.1073/pnas.0604554103
发表时间：
2006-07-18
影响因子：
11.1
作者：
Iniesta, Antonio A.;McGrath, Patrick T.;Shapiro, Lucy
通讯作者：
Shapiro, Lucy
影响因子：
3.7
作者：
Fernandez-Fernandez C;Gonzalez D;Collier J
通讯作者：
Collier J
影响因子：
11.4
作者：
Collier, J;Murray, SR;Shapiro, L
通讯作者：
Shapiro, L