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Journal ArticleDOI

Commitment to a cellular transition precedes genome-wide transcriptional change

19 Aug 2011-Molecular Cell (NIH Public Access)-Vol. 43, Iss: 4, pp 515-527
TL;DR: It is found that genes within the G1/S regulon have a well-defined distribution of transcriptional activation times, which results in a logical OR function for gene expression and partially explains activation timing.
About: This article is published in Molecular Cell.The article was published on 2011-08-19 and is currently open access. It has received 84 citations till now. The article focuses on the topics: E2F Transcription Factors & Regulon.
Citations
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Journal ArticleDOI
TL;DR: The complex molecular mechanisms that control the temporal order of transcriptional activation and inactivation, determine distinct functional subgroups of genes and link cell cycle-dependent transcription to DNA replication stress in yeast and mammals are revealed.
Abstract: The accurate transition from G1 phase of the cell cycle to S phase is crucial for the control of eukaryotic cell proliferation, and its misregulation promotes oncogenesis. During G1 phase, growth-dependent cyclin-dependent kinase (CDK) activity promotes DNA replication and initiates G1-to-S phase transition. CDK activation initiates a positive feedback loop that further increases CDK activity, and this commits the cell to division by inducing genome-wide transcriptional changes. G1-S transcripts encode proteins that regulate downstream cell cycle events. Recent work is beginning to reveal the complex molecular mechanisms that control the temporal order of transcriptional activation and inactivation, determine distinct functional subgroups of genes and link cell cycle-dependent transcription to DNA replication stress in yeast and mammals.

1,097 citations

Journal ArticleDOI
TL;DR: Examination of size-sensing models based on spatial gradients and molecular titration, coupled with elucidation of the pathways responsible for nutrient-modulated target size, may reveal the fundamental principles of eukaryotic cell size control.

295 citations


Cites background from "Commitment to a cellular transition..."

  • ...Despite co-regulation, the transcription of the regulon through the mitotic cell cycle is temporally organized: the G1 cyclin CLN1 is the earliest activated gene (CLN2 is also relatively early) implying that G1 cyclin positive feedback is initiated prior to genome-wide changes to the transcriptional program [122]....

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Journal ArticleDOI
TL;DR: Work from several organisms has revealed a conserved strategy whereby inactive replication complexes are assembled onto DNA during periods of low CDK and high APC activity but are competent to execute genome duplication only when these activities are reversed.
Abstract: DNA replication is tightly controlled in eukaryotic cells to ensure that an exact copy of the genetic material is inherited by both daughter cells. Oscillating waves of cyclin-dependent kinase (CDK) and anaphase-promoting complex/cyclosome (APC/C) activities provide a binary switch that permits the replication of each chromosome exactly once per cell cycle. Work from several organisms has revealed a conserved strategy whereby inactive replication complexes are assembled onto DNA during periods of low CDK and high APC activity but are competent to execute genome duplication only when these activities are reversed. Periods of high CDK and low APC/C serve an essential function by blocking reassembly of replication complexes, thereby preventing rereplication. Higher eukaryotes have evolved additional CDK-independent mechanisms for preventing rereplication.

228 citations


Cites background from "Commitment to a cellular transition..."

  • ...Whereas SBF activates transcription of Cln cyclins (Nasmyth and Dirick 1991; Spellman et al. 1998; Eser et al. 2011), MBF promotes transcription of Clb5 along with other replication genes (Lowndes et al. 1992; Koch et al. 1993; Spellman et al. 1998; Eser et al. 2011)....

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Journal ArticleDOI
TL;DR: A quantitative single-cell analysis of commitment dynamics during the mating-mitosis switch in budding yeast shows that specification and maintenance of a cellular state are performed by distinct interactions, which are likely a consequence of disparate reaction rates and may be a general feature of the interlinked regulatory networks responsible for selecting cell fates.

139 citations


Cites background from "Commitment to a cellular transition..."

  • ...After a simple subtraction, the Whi5-GFP signal does not interfere with the CLN2pr-GFP signal, and vice versa (Skotheim et al., 2008)....

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  • ...In a related paper appearing in this issue, we show that increased expression of the G1 cyclins CLN1 and CLN2 precedes activation of the bulk of the >200 coregulated genes, implying that genomewide changes in transcription depend on cell cycle commitment (Eser et al., 2011)....

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Journal ArticleDOI
TL;DR: It is shown that a central metabolite of glucose catabolism, acetyl-CoA, induces CLN3 transcription by promoting the acetylation of histones present in its regulatory region.
Abstract: In budding yeast cells, nutrient repletion induces rapid exit from quiescence and entry into a round of growth and division. The G1 cyclin CLN3 is one of the earliest genes activated in response to nutrient repletion. Subsequent to its activation, hundreds of cell-cycle genes can then be expressed, including the cyclins CLN1/2 and CLB5/6. Although much is known regarding how CLN3 functions to activate downstream targets, the mechanism through which nutrients activate CLN3 transcription in the first place remains poorly understood. Here we show that a central metabolite of glucose catabolism, acetyl-CoA, induces CLN3 transcription by promoting the acetylation of histones present in its regulatory region. Increased rates of acetyl-CoA synthesis enable the Gcn5p-containing Spt-Ada-Gcn5-acetyltransferase transcriptional coactivator complex to catalyze histone acetylation at the CLN3 locus alongside ribosomal and other growth genes to promote entry into the cell division cycle.

138 citations

References
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Journal ArticleDOI
TL;DR: A comprehensive catalog of yeast genes whose transcript levels vary periodically within the cell cycle is created, and it is found that the mRNA levels of more than half of these 800 genes respond to one or both of these cyclins.
Abstract: We sought to create a comprehensive catalog of yeast genes whose transcript levels vary periodically within the cell cycle. To this end, we used DNA microarrays and samples from yeast cultures sync...

5,176 citations

Journal ArticleDOI
16 Oct 2003-Nature
TL;DR: A Saccharomyces cerevisiae fusion library is created where each open reading frame is tagged with a high-affinity epitope and expressed from its natural chromosomal location, and it is found that about 80% of the proteome is expressed during normal growth conditions.
Abstract: The availability of complete genomic sequences and technologies that allow comprehensive analysis of global expression profiles of messenger RNA have greatly expanded our ability to monitor the internal state of a cell. Yet biological systems ultimately need to be explained in terms of the activity, regulation and modification of proteins--and the ubiquitous occurrence of post-transcriptional regulation makes mRNA an imperfect proxy for such information. To facilitate global protein analyses, we have created a Saccharomyces cerevisiae fusion library where each open reading frame is tagged with a high-affinity epitope and expressed from its natural chromosomal location. Through immunodetection of the common tag, we obtain a census of proteins expressed during log-phase growth and measurements of their absolute levels. We find that about 80% of the proteome is expressed during normal growth conditions, and, using additional sequence information, we systematically identify misannotated genes. The abundance of proteins ranges from fewer than 50 to more than 10(6) molecules per cell. Many of these molecules, including essential proteins and most transcription factors, are present at levels that are not readily detectable by other proteomic techniques nor predictable by mRNA levels or codon bias measurements.

3,894 citations


"Commitment to a cellular transition..." refers background in this paper

  • ...We analyzed protein accumulation in ten strains expressing C-terminal GFP fusion proteins from the endogenous loci (Ghaemmaghami et al., 2003) and two strains containing an integrated CLN1 or CLN2 promoter driving the expression of a destabilized VenusPEST (Mateus and Avery 2000)....

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Journal ArticleDOI
TL;DR: This work applied new algorithms for systematically detecting network motifs to one of the best-characterized regulation networks, that of direct transcriptional interactions in Escherichia coli, and finds that much of the network is composed of repeated appearances of three highly significant motifs.
Abstract: Little is known about the design principles1,2,3,4,5,6,7,8,9,10 of transcriptional regulation networks that control gene expression in cells. Recent advances in data collection and analysis2,11,12, however, are generating unprecedented amounts of information about gene regulation networks. To understand these complex wiring diagrams1,2,3,4,5,6,7,8,9,10,13, we sought to break down such networks into basic building blocks2. We generalize the notion of motifs, widely used for sequence analysis, to the level of networks. We define 'network motifs' as patterns of interconnections that recur in many different parts of a network at frequencies much higher than those found in randomized networks. We applied new algorithms for systematically detecting network motifs to one of the best-characterized regulation networks, that of direct transcriptional interactions in Escherichia coli3,6. We find that much of the network is composed of repeated appearances of three highly significant motifs. Each network motif has a specific function in determining gene expression, such as generating temporal expression programs and governing the responses to fluctuating external signals. The motif structure also allows an easily interpretable view of the entire known transcriptional network of the organism. This approach may help define the basic computational elements of other biological networks.

3,117 citations

Journal ArticleDOI
03 Nov 1989-Science
TL;DR: It appears that some checkpoints are eliminated during the early embryonic development of some organisms; this fact may pose special problems for the fidelity of embryonic cell division.
Abstract: The events of the cell cycle of most organisms are ordered into dependent pathways in which the initiation of late events is dependent on the completion of early events. In eukaryotes, for example, mitosis is dependent on the completion of DNA synthesis. Some dependencies can be relieved by mutation (mitosis may then occur before completion of DNA synthesis), suggesting that the dependency is due to a control mechanism and not an intrinsic feature of the events themselves. Control mechanisms enforcing dependency in the cell cycle are here called checkpoints. Elimination of checkpoints may result in cell death, infidelity in the distribution of chromosomes or other organelles, or increased susceptibility to environmental perturbations such as DNA damaging agents. It appears that some checkpoints are eliminated during the early embryonic development of some organisms; this fact may pose special problems for the fidelity of embryonic cell division.

3,048 citations


"Commitment to a cellular transition..." refers background in this paper

  • ...Checkpoints use designated regulatory molecules to restrain cell-cycle progression until a set of criteria are satisfied (Hartwell and Weinert 1989)....

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Journal ArticleDOI
TL;DR: The genome-wide characterization of mRNA transcript levels during the cell cycle of the budding yeast S. cerevisiae indicates a mechanism for local chromosomal organization in global mRNA regulation and links a range of human genes to cell cycle period-specific biological functions.

2,232 citations


"Commitment to a cellular transition..." refers background in this paper

  • ...This extensive oscillation entails 10%–20% of all Caulobacter and budding-yeast genes (Cho et al., 1998; Spellman et al., 1998; Laub et al., 2000)....

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