The overall goal of this research is to define the origins and the consequences of errors in information transfer from DNA to protein in the perpetuation and perturbation of genetic regulatory networks that generate stable phenotypes in cellular lineages of Escherichia coli, e.g. bistable switches. Bistability has been proposed as a mechanism for decision-making and memory in gene circuits, relying on positive feedback loops between transcription factors of low abundance. The central hypothesis of this proposal is that transient errors in the information transfer from DNA to protein contribute to protein fluctuation (molecular noise) and that these errors can cause heritable non-genetic phenotypic heterogeneity, when associated with bistable regulatory networks. Specifically, we propose that the transient disappearance of functional protein (in our case, a repressor that negatively regulates the expression of other genes) due to errors in transcription, translation, or protein folding can produce a heritable phenotypic change in genetically identical cells growing in the same environment. To capture and quantify transient events from such errors, two well characterized bistable systems will be used, the lactose operon and the lambda switch. In these systems, the stochastic switching from one phenotypic state to the alternative phenotypic state will be an indicator of molecular noise. This work will illuminate the fundamental cell/molecular biology of protein-based epigenetic switches, which are likely to be critical to many fundamental aspects of biology and medicine including cancer, aging, prion genesis, and pluripotency of stem cells.

Public Health Relevance

To generate diversity, cells run specific programs orchestrated by specific protein regulators. Sometimes the making of these proteins is erroneous, leading to dysfunction of the program, and loss of cellular identity. Our study aims to understand the origin and consequence of these errors on these protein regulators.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM088653-03
Application #
8306132
Study Section
Prokaryotic Cell and Molecular Biology Study Section (PCMB)
Program Officer
Sledjeski, Darren D
Project Start
2010-08-01
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$294,377
Indirect Cost
$106,277
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Marciano, David C; Lua, Rhonald C; Herman, Christophe et al. (2016) Cooperativity of Negative Autoregulation Confers Increased Mutational Robustness. Phys Rev Lett 116:258104
Grace, Elicia D; Gopalkrishnan, Saumya; Girard, Mary E et al. (2015) Activation of the σE-dependent stress pathway by conjugative TraR may anticipate conjugational stress. J Bacteriol 197:924-31
Gordon, Alasdair J E; Satory, Dominik; Halliday, Jennifer A et al. (2015) Lost in transcription: transient errors in information transfer. Curr Opin Microbiol 24:80-7
Satory, Dominik; Gordon, Alasdair J E; Wang, Mengyu et al. (2015) DksA involvement in transcription fidelity buffers stochastic epigenetic change. Nucleic Acids Res 43:10190-9
Zhang, Yan; Mooney, Rachel A; Grass, Jeffrey A et al. (2014) DksA guards elongating RNA polymerase against ribosome-stalling-induced arrest. Mol Cell 53:766-78
Bednarz, Michael; Halliday, Jennifer A; Herman, Christophe et al. (2014) Revisiting bistability in the lysis/lysogeny circuit of bacteriophage lambda. PLoS One 9:e100876
Gordon, Alasdair J E; Satory, Dominik; Wang, Mengyu et al. (2014) Removal of 8-oxo-GTP by MutT hydrolase is not a major contributor to transcriptional fidelity. Nucleic Acids Res 42:12015-26
Marciano, David C; Lua, Rhonald C; Katsonis, Panagiotis et al. (2014) Negative feedback in genetic circuits confers evolutionary resilience and capacitance. Cell Rep 7:1789-95
Gordon, Alasdair J E; Satory, Dominik; Halliday, Jennifer A et al. (2013) Heritable change caused by transient transcription errors. PLoS Genet 9:e1003595
Shee, Chandan; Cox, Ben D; Gu, Franklin et al. (2013) Engineered proteins detect spontaneous DNA breakage in human and bacterial cells. Elife 2:e01222

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