Bacterial epigenetic memory of heat shock response

About This Grant

SUMMARY/ABSTRACT Treatment of pathogens depends upon their genetic resistance to antibiotics as well as non-genetic heteroresistance, but it is unclear whether there are inherited non-genetic factors that influence their susceptibility. One physiological change known to influence antibiotic sensitivity is the heat shock response: the coordinated upregulation of protein chaperones that reverse misfolded protein aggregates. Misfolded proteins sensitize cells to antibiotics, such that concurrent treatment with heat potentiates their use, whereas a pre- exposure to heat leaves cells better able to handle a later challenge. Although eukaryotes have epigenetic mechanisms to pass their heat shock response to later generations, to date no report of a similar phenomenon has been made for bacteria. Our proposed project takes advantage of our discovery of epigenetic memory of heat shock response in Methylobacterium extorquens. We uncovered this phenomenon using a novel, high-throughput assay for epigenetic inheritance and collateral effects in alternative environments. Exposure to a heat shock leaves an imprint on cells 15 generations later that improves their ability to handle another heat shock but otherwise decreases their growth in all other environments. We hypothesize that the formation of protein aggregates triggers memory, and that memory is maintained via a heritable, alternative DNA methylation at one or more loci, with that methylation state resulting in a higher baseline expression of chaperones and other heat shock proteins. The overall objective of this proposed research is to understand how the heat shock response is inherited and how it leads to altered antibiotic sensitivity. The outcome of this proposed work will be the development of a general framework and novel methodology that can be used to explore the potential for epigenetic memory of heat shock across bacteria. The intersection between multiple empirical approaches and statistical analysis of the quantitative physiological data provides an excellent trans-disciplinary training ground for undergraduates. The positive impacts of this research will be to weave epigenetic inheritance into more effective antibiotic treatment strategies.