Phenotypic variation is ubiquitous in biology and is often traceable to underlying genetic and environmental variation. However, even genetically identical organisms in homogenous environments vary, suggesting that random processes may play an important role in generating phenotypic diversity;indeed, stochastic effects in gene expression can generate beneficial phenotypic variation in microbes. Few studies have explored the impact of stochastic fluctuations in gene expression on phenotypic variation and cell fate decisions in multicellular organisms. For the last ten years, the van Oudenaarden laboratory has intensively studied stochastic gene expression in microbial systems and more recently started to apply these concepts to multicellular organisms and stem cels. One of the major lessons learned from our work and others is that microbial systems tend to exploit stochastic gene expression by introducing phenotypic diversity into the population without the need to resort to irreversible genome modifications. This non-genetic variability can increase the fitness of the population particularly in fluctuating environments. This makes sense for microbes continuously challenged by unpredictable environments. However it is an open question whether stochastic gene expression benefits or hinders decision-making by cells in a developing organism. The overarching goal of this proposal is to understand how stochastic gene expression is controlled, or utilized, during development and stem cell differentiation using the nematode worm Caenorhabditis elegans and murine embryonic stem cells as experimental model systems. During the last three years at MIT my laboratory has developed an expertise in working with these experimental model systems. My laboratory will use a combination of quantitative experiments, theoretical and computational approaches, and the development of novel technology to develop a quantitative understanding of the origins and consequences of stochastic gene expression during development and stem cell differentiation.

Public Health Relevance

The synthesis of important molecules such as proteins and RNAs in the cell is a noisy process. These random fluctuations might hinder the proper development of an embryo or maintenance of adult tissue. In this proposal we study the mechanisms that cells use to dampen and control these random fluctuations. It might be that in certain diseases these control mechanisms do not operate correctly resulting in pathological outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM068957-10
Application #
8474778
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Brazhnik, Paul
Project Start
2003-06-15
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
10
Fiscal Year
2013
Total Cost
$278,154
Indirect Cost
$89,979
Name
Massachusetts Institute of Technology
Department
Physics
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Slavov, Nikolai; Budnik, Bogdan A; Schwab, David et al. (2014) Constant growth rate can be supported by decreasing energy flux and increasing aerobic glycolysis. Cell Rep 7:705-14
Junker, Jan Philipp; Peterson, Kevin A; Nishi, Yuichi et al. (2014) A predictive model of bifunctional transcription factor signaling during embryonic tissue patterning. Dev Cell 31:448-60
Kim, Dong hyun; Grun, Dominic; van Oudenaarden, Alexander (2013) Dampening of expression oscillations by synchronous regulation of a microRNA and its target. Nat Genet 45:1337-44
Fang, Miaoqing; Xie, Huangming; Dougan, Stephanie K et al. (2013) Stochastic cytokine expression induces mixed T helper cell States. PLoS Biol 11:e1001618
Teytelman, Leonid; Thurtle, Deborah M; Rine, Jasper et al. (2013) Highly expressed loci are vulnerable to misleading ChIP localization of multiple unrelated proteins. Proc Natl Acad Sci U S A 110:18602-7
Tan, Rui Zhen; Ji, Ni; Mentink, Remco A et al. (2013) Deconvolving the roles of Wnt ligands and receptors in sensing and amplification. Mol Syst Biol 9:631
Tan, Rui Zhen; van Oudenaarden, Alexander (2010) Transcript counting in single cells reveals dynamics of rDNA transcription. Mol Syst Biol 6:358
Dong, Guogang; Yang, Qiong; Wang, Qiang et al. (2010) Elevated ATPase activity of KaiC applies a circadian checkpoint on cell division in Synechococcus elongatus. Cell 140:529-39
Tsang, John S; Ebert, Margaret S; van Oudenaarden, Alexander (2010) Genome-wide dissection of microRNA functions and cotargeting networks using gene set signatures. Mol Cell 38:140-53
Yang, Qiong; Pando, Bernardo F; Dong, Guogang et al. (2010) Circadian gating of the cell cycle revealed in single cyanobacterial cells. Science 327:1522-6

Showing the most recent 10 out of 23 publications