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Award Abstract #1147498

CAREER: Towards a quantitative picture of gene regulation in individual cells

NSF Org: PHY
Division Of Physics
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Initial Amendment Date: March 14, 2013
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Latest Amendment Date: June 2, 2016
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Award Number: 1147498
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Award Instrument: Continuing grant
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Program Manager: Krastan B. Blagoev
PHY Division Of Physics
MPS Direct For Mathematical & Physical Scien
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Start Date: March 15, 2013
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End Date: February 28, 2018 (Estimated)
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Awarded Amount to Date: $745,208.00
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Investigator(s): Ido Golding golding@bcm.edu (Principal Investigator)
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Sponsor: Baylor College of Medicine
ONE BAYLOR PLAZA
HOUSTON, TX 77030-3411 (713)798-1297
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NSF Program(s): Genetic Mechanisms,
PHYSICS OF LIVING SYSTEMS
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Program Reference Code(s): 1045, 1112, 7237, 7465, 8007
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Program Element Code(s): 1112, 7246

ABSTRACT

In this project the PI will create a quantitative description of the "gene regulation function", i.e. the variation of the transcription of a given gene with the amount of its regulating transcription factor in individual cells. Specifically, the PI will quantify how gene activity, in the form of the discrete time-series of mRNA production events, is modulated by varying concentrations of transcription factors. The PI will examine three paradigmatic gene circuits of increasing organismal complexity, from bacteria to mammals. To perform these measurements, he will use a synthesis of traditional biochemistry and molecular biology techniques, single-cell fluorescence microscopy, advanced image processing and data analysis algorithms, accompanied by coarse-grained theoretical models and stochastic simulations of the underlying kinetics. A significant intellectual outcome of this project will be the first precise quantitative description of the gene regulation function at the level of individual cells, individual transcription events and absolute numbers of proteins and RNA, in genetically unperturbed systems. This mesoscopic description will provide a bridge between two existing levels of description: the molecular (microscopic) level, at which a wealth of information is available, largely through classical biochemistry and biophysics in vitro; and the macroscopic level of gene-network topologies, obtained mostly through classical genetics, but which lacks any quantitative details on the regulatory interactions between elements. The PI and Dr. Sokac in collaboration with Rice University will provide a one-week wet-lab based teaser course for quantitative undergraduates (Q-students) from math, physics, chemistry, computer science and engineering. The goals of the course are to show Q-students how quantitative methods apply to biology, and encourage them to pursue independent research projects. Q-students will be coached on how to find undergrad research positions in labs at the Texas Medical Center, and once placed, they will receive support from mentors and colleagues in a weekly evening discussion group run by the PIs. Ultimately, the goal is to recruit Q-students to careers in biological research.

This project is being jointly supported by the Physics of Living Systems program in the Division of Physics and the Genetic Mechanisms Program in the Division of Molecular and Cellular Biosciences.


PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH

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(Showing: 1 - 10 of 22)
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L Zheng, LA Sepúlveda, RC Lua, O Lichtarge, I Golding, AM Sokac. "The Maternal-to-Zygotic Transition Targets Actin to Promote Robustness during Morphogenesis," PLoS genetics, v.9, 2013, p. e1003901. 

SO Skinner, LA Sepúlveda, H Xu, I Golding. "Measuring mRNA copy number in individual Escherichia coli cells using single-molecule fluorescent in situ hybridization," Nature protocols, v.8, 2013, p. 1100. 

A Sanchez, I Golding. "Genetic Determinants and Cellular Constraints in Noisy Gene Expression," Science, 2013.

AJE Gordon, D Satory, M Wang, JA Halliday, I Golding, C Herman. "Removal of 8-oxo-GTP by MutT hydrolase is not a major contributor to transcriptional fidelity," Nucleic acids research, v.42, 2014, p. 12015. 

L Figard, H Xu, HG Garcia, I Golding, AM Sokac. "The Plasma Membrane Flattens Out to Fuel Cell-Surface Growth during Drosophila Cellularization," Developmental Cell, v.27, 2013. 

L Zheng, LA Sepúlveda, RC Lua, O Lichtarge, I Golding, AM Sokac. "The Maternal-to-Zygotic Transition
Targets Actin to Promote Robustness during Morphogenesis," PLoS genetics, v.9, 2013, p. e1003901.

M Bednarz, JA Halliday, C Herman, I Golding. "Revisiting Bistability in the Lysis/Lysogeny Circuit of Bacteriophage Lambda," PLoS one, v.9, 2014, p. e100876.

PJ Mears, S Koirala, CV Rao, I Golding, YR Chemla. "Escherichia coli swimming is robust against variations in flagellar number," eLife, v.2, 2014, p. 3:e01916. 

S Koirala, P Mears, M Sim, I Golding, YR Chemla, PD Aldridge, CV Rao. "A Nutrient-Tunable Bistable Switch Controls Motility in Salmonella enterica Serovar Typhimurium," mBio, v.5, 2014, p. e01611.

SO Skinner, LA Sepúlveda, H Xu, I Golding. "Measuring mRNA copy number in individual Escherichia coli cells using single-molecule fluorescent in situ hybridization," Nature protocols, v.8, 2013, p. 1100.


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