The ability of a cell to grow and divide in variable environments is contingent on its ability to sense and respond appropriately to external change. Throughout eukaryotes, mitogen activated protein kinase pathways (MAPK) are frequently used to link external changes to downstream cellular responses, which necessarily includes cell cycle regulation. In this proposal, we focus on control of the cell cycle by the pheromone-induced MAPK pathway in budding yeast. Information about pheromone concentration is integrated in G1 phase, prior to the 'Start'of the cell cycle. Whereas pre-Start early G1 cells arrest their cell cycle directly when exposed to mating pheromone, post-Start late G1 cells are unaffected until the subsequent cycle. Due to our extensive molecular knowledge of both the genes involved and their biochemical interactions, Start serves as a model for cell cycle commitment in eukaryotes. Here, we aim to apply dynamical systems theory to attain a comprehensive understanding of checkpoint control and advance our understanding of genetic circuits governing cellular transitions. More specifically, we aim to understand how genetic circuits are implemented to generate mutually exclusive cell fates, and, once a particular fate is selected, how large transcriptional programs are seamlessly actuated to effect cellular transitions. Across yeasts, the core function of the genetic control network at the interface between the pheromone-induced MAPK pathway and the cell cycle, i.e., to separate mating from mitosis, remains unchanged. However, there has been dramatic evolution of the components of both the cell cycle and MAPK pathways. By initiating a parallel set of experiments using the fission yeast model, we aim to investigate the hypothesis that evolution has acted to conserve the dynamical systems properties rather than the individual parts of the regulatory network. Our experimental program is comprised of both single-cell microscopy and novel bioinformatic algorithms to analyze genome-wide datasets. Notably, we employ a microfluidic platform that allows time-lapse phase and fluorescence imaging during rapid exposure to mating pheromone. Our algorithms and analysis will be applicable to a wide range of systems.

Public Health Relevance

Genes involved in the core processes of cell cycle control are frequently mutated in cancers. Since cell cycle regulation is highly conserved across eukaryotes, the concepts and techniques developed in the proposed research are likely to provide a broader and deeper understanding of the human system and to give insight into oncogenesis. Project Narrative Genes involved in the core processes of cell cycle control are frequently mutated in cancers. Since cell cycle regulation is highly conserved across eukaryotes, the concepts and techniques developed in the proposed research are likely to provide a broader and deeper understanding of the human system and to give insight into oncogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM092925-05
Application #
8708114
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Hamlet, Michelle R
Project Start
2010-08-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
$297,955
Indirect Cost
$109,855
Name
Stanford University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Schwarz, Clayton; Johnson, Amy; Kõivomägi, Mardo et al. (2018) A Precise Cdk Activity Threshold Determines Passage through the Restriction Point. Mol Cell 69:253-264.e5
Atay, Oguzhan; Skotheim, Jan M (2017) Spatial and temporal signal processing and decision making by MAPK pathways. J Cell Biol 216:317-330
Eser, Umut; Chandler-Brown, Devon; Ay, Ferhat et al. (2017) Form and function of topologically associating genomic domains in budding yeast. Proc Natl Acad Sci U S A 114:E3061-E3070
Medina, Edgar M; Turner, Jonathan J; Gordân, Raluca et al. (2016) Punctuated evolution and transitional hybrid network in an ancestral cell cycle of fungi. Elife 5:
Atay, Oguzhan; Doncic, Andreas; Skotheim, Jan M (2016) Switch-like Transitions Insulate Network Motifs to Modularize Biological Networks. Cell Syst 3:121-132
Treutlein, Barbara; Lee, Qian Yi; Camp, J Gray et al. (2016) Dissecting direct reprogramming from fibroblast to neuron using single-cell RNA-seq. Nature 534:391-5
Doncic, Andreas; Atay, Oguzhan; Valk, Ervin et al. (2015) Compartmentalization of a bistable switch enables memory to cross a feedback-driven transition. Cell 160:1182-95
Zatulovskiy, Evgeny; Skotheim, Jan M (2015) Mitosis is swell. J Cell Biol 211:733-5
Atay, Oguzhan; Skotheim, Jan M (2014) Modularity and predictability in cell signaling and decision making. Mol Biol Cell 25:3445-50
Doncic, Andreas; Skotheim, Jan M (2013) Feedforward regulation ensures stability and rapid reversibility of a cellular state. Mol Cell 50:856-68

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