Molecular Noise, Transcription Errors and Heritable Phenotypic Change

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DESCRIPTION (provided by applicant): 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.