Phenotypic inheritance relies on the correct transfer of the genetic (DNA) and epigenetic (heritable expression state) information. It is well established that DNA alteration can heritably change the phenotype of a cell, but what is less clear is what triggers heritable epigenetic change. Seminal work in bacteria has highlighted the importance of genetic networks in epigenetic inheritance. To generate stable phenotypic diversity in a population, cells with identical genomes can be differently programmed by transcription factors connected in a positive feedback loop, allowing the stable expression of two alternative phenotypes. Regulatory proteins associated with these molecular switches are often present in low numbers and therefore, subject to fluctuation or "molecular noise". Therefore, the strategy used by a genetic network to control levels of its key regulators is fundamental to the understanding of the potential sources of dysregulation. Molecular noise in gene expression is universal and arises as a result of the stochastic nature of transcription and translation and can directly perturb the behavior of genetic-regulatory-networks generating phenotypic diversity. My lab is investigating the role of transient errors in information transfer (transcription, translation, or post-translational modification errors) in the dysregulation of bistable genetic networks leading to heritable change in phenotype. To study the contribution of information transfer errors on the generation of heritable phenotypic diversity, we are using classical bistable switches in the bacterium Escherichia coli; the bacteriophage lambda genetic switch; and the Lac operon. With the exception of Prion inheritance, the idea that transient errors in information transfer from RNA to protein can have heritable consequences without any alteration of the DNA sequence has not been considered before, but our work challenge this idea by showing that transient alteration of autocatalytic systems can have profound heritable consequences. Thus, our work suggests that transient errors in information transfer may be an important mechanism of epigenetic change and should be considered as the causative agent for many human diseases ranging from the progression of AIDS to devastating neurodegenerative diseases.
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Training in Precision Environmental Health Sciences (TPEHS)
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