Daughter-specific transcription factors regulate cell size control in budding yeast.
Daughter-specific transcription factors regulate cell size control in budding yeast.
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DOI：
10.1371/journal.pbio.1000221
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发表时间：
2009-10
期刊：
影响因子：
9.8
通讯作者：
Cross FR
中科院分区：
文献类型：
--
作者：
Di Talia S;Wang H;Skotheim JM;Rosebrock AP;Futcher B;Cross FR
芽殖酵母中细胞命运决定子的不对称定位导致细胞周期的不对称控制。在芽殖酵母中，不对称细胞分裂产生较大的母细胞和较小的子细胞，由于子细胞特异性转录因子Ace2和Ash1，它们转录不同的基因。在起始检查点的细胞大小控制一直被认为是细胞周期G1期长度的主要调节因子，导致较小的子细胞中的G1期较长。我们最近的数据证实了这一概念，使用定量延时显微镜。然而，有人提出，女儿特异性，ACE 2依赖性抑制G1期细胞周期蛋白CLN3的表达在延迟女儿在G1期起主导作用。我们想调和这两个不同的观点的起源长子G1倍。我们使用荧光标记的芽殖酵母的单细胞延时成像定量大小控制，在存在或不存在的子体特异性转录调节因子Ace2和Ash1的情况下。Ace2和Ash1对于有效的大小控制不是必需的，但是它们将有效的大小控制的域转移到更大的单元大小，从而增加了子体中开始的单元大小要求。微阵列和染色质免疫沉淀实验表明，Ace2和Ash1是G1期细胞周期蛋白基因CLN3的直接转录调节因子。在异位启动子和CLN3启动子中具有突变的Ace2和Ash1位点的细胞中表达滴定水平的CLN3的细胞大小控制的定量显示，Ace2和Ash1对CLN3表达的调节可以解释在母亲和女儿中响应于细胞大小的Start的差异调节。我们展示了子细胞特异性转录程序如何与内在细胞大小控制相互作用，以差异化调节母细胞和子细胞中的启动。这项工作从机制上证明了细胞命运决定因素的不对称定位如何导致细胞周期的细胞类型特异性调节。不对称细胞分裂是产生分化细胞的普遍机制。这种分裂的后代通常可以显示差异的细胞周期调节。这项研究解决了如何在一个单一的分裂后代基因表达的差异调节可以改变细胞周期控制。在芽殖酵母中，不对称的细胞分裂产生一个较大的“母”细胞和一个较小的“子”细胞。基因表达的调节也是不对称的，因为两个转录因子Ace2和Ash1特异性地定位于子体。长期以来，细胞大小被认为对酵母细胞周期的调节很重要。我们的工作表明，Ace2和Ash1调节子细胞的大小控制：子细胞“解释”它们的大小较小，使大小控制更加严格，并相对于相同大小的母细胞延迟细胞周期承诺。细胞大小的这种不对称解释与Ace2和Ash1对G1期细胞周期蛋白CLN3的差异调节有关，至少部分是通过这些因子与CLN3启动子的直接结合。CLN3是Start（酵母细胞周期的起始点）的最上游调节剂，CLN3的差异调节解释了芽殖酵母母细胞和子细胞中Start的大部分或全部不对称调节。
The asymmetric localization of cell fate determinants results in asymmetric cell cycle control in budding yeast. In budding yeast, asymmetric cell division yields a larger mother and a smaller daughter cell, which transcribe different genes due to the daughter-specific transcription factors Ace2 and Ash1. Cell size control at the Start checkpoint has long been considered to be a main regulator of the length of the G1 phase of the cell cycle, resulting in longer G1 in the smaller daughter cells. Our recent data confirmed this concept using quantitative time-lapse microscopy. However, it has been proposed that daughter-specific, Ace2-dependent repression of expression of the G1 cyclin CLN3 had a dominant role in delaying daughters in G1. We wanted to reconcile these two divergent perspectives on the origin of long daughter G1 times. We quantified size control using single-cell time-lapse imaging of fluorescently labeled budding yeast, in the presence or absence of the daughter-specific transcriptional regulators Ace2 and Ash1. Ace2 and Ash1 are not required for efficient size control, but they shift the domain of efficient size control to larger cell size, thus increasing cell size requirement for Start in daughters. Microarray and chromatin immunoprecipitation experiments show that Ace2 and Ash1 are direct transcriptional regulators of the G1 cyclin gene CLN3. Quantification of cell size control in cells expressing titrated levels of Cln3 from ectopic promoters, and from cells with mutated Ace2 and Ash1 sites in the CLN3 promoter, showed that regulation of CLN3 expression by Ace2 and Ash1 can account for the differential regulation of Start in response to cell size in mothers and daughters. We show how daughter-specific transcriptional programs can interact with intrinsic cell size control to differentially regulate Start in mother and daughter cells. This work demonstrates mechanistically how asymmetric localization of cell fate determinants results in cell-type-specific regulation of the cell cycle. Asymmetric cell division is a universal mechanism for generating differentiated cells. The progeny of such divisions can often display differential cell cycle regulation. This study addresses how differential regulation of gene expression in the progeny of a single division can alter cell cycle control. In budding yeast, asymmetric cell division yields a bigger ‘mother’ cell and a smaller ‘daughter’ cell. Regulation of gene expression is also asymmetric because two transcription factors, Ace2 and Ash1, are specifically localized to the daughter. Cell size has long been proposed as important for the regulation of the cell cycle in yeast. Our work shows that Ace2 and Ash1 regulate size control in daughter cells: daughters ‘interpret’ their size as smaller, making size control more stringent and delaying cell cycle commitment relative to mother cells of the same size. This asymmetric interpretation of cell size is associated with differential regulation of the G1 cyclin CLN3 by Ace2 and Ash1, at least in part via direct binding of these factors to the CLN3 promoter. CLN3 is the most upstream regulator of Start, the initiation point of the yeast cell cycle, and differential regulation of CLN3 accounts for most or all asymmetric regulation of Start in budding yeast mother and daughter cells.
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影响因子：
64.5
作者：
Colman-Lerner, A;Chin, TE;Brent, R
通讯作者：
Brent, R
影响因子：
4.8
作者：
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影响因子：
10.5
作者：
DOHRMANN, PR;BUTLER, G;STILLMAN, DJ
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STILLMAN, DJ
影响因子：
56.9
作者：
HARTWELL, LH;CULOTTI, J;REID, BJ
通讯作者：
REID, BJ
影响因子：
5.3
作者：
CROSS, FR
通讯作者：
CROSS, FR