Stress response roles in driving meiotic cellular remodeling
Through meiotic differentiation, in the absence of dynamic external stimuli, we have observed timed induction of prominent stress pathway factors . Many of these pathways include post-translational regulation, suggesting that these measurements underestimate their dynamic control. Nonetheless, the striking and stereotypical regulation of stress programs in meiosis suggests that while harsh exogenous treatment including heat and drugs may have enabled their discovery, categorization of such pathways as 'stress-responsive' may not reflect their sole or even major physiological role.
Stress responses are turned on at discrete times in meiosis. Translation of various factors involved in canonical stress responses over meiosis is shown. These factors are induced at the level of protein synthesis in the absence of their characterized external stimulus. To the right is a more detailed view of UPR induction, as determined by Hac1 translation and splicing of the HAC1 message.
The DNA damage response is a case in which a conserved and dedicated role in meiotic differentiation is clear. In fact, studies of meiotic recombination have revealed general principles of DNA repair. We propose that this case reflects a broad theme. For instance, while central components of the Unfolded Protein Response (UPR) are conserved from yeast to human,they are dispensable for growth in yeast. Thus, study of the yeast UPR has relied on non-physiological experimentation, including the use of inhibitors of ER (endoplasmic reticulum) folding such as dithiothreitol (DTT). Drug-based studies have yielded significant insight into UPR function, but meiotic UPR induction provides the first physiological yeast model of timed induction akin to that seen in differentiating mammalian cells. This allows us access to previously inaccessible questions about natural UPR signaling, while also allowing an opportunity to learn about the role of ER remodeling in meiosis.
Stress pathways and cellular rejuvenation (with Ünal lab)
In an exciting Br-Ün Lab collaboration, we are expanding our studies of stress pathway activation in meiosis to explore the role of these pathways in cellular rejuvenation. The Ünal lab has shown that the meiotic gene expression program downstream of the transcription factor Ndt80 can reset cellular lifespan when induced in mitotic cells. We believe that moderate stress pathway activation, or hormesis, causes the rejuvenation that naturally occurs in meiosis/gametogenesis and that can be recapitulated in meiosis by Ndt80 expression, a hypothesis that our Br-Ün team is interrogating.
Ndt80 drives cellular rejuvenation. Schematic of results from Ünal, Kinde, and Amon. Science. 2011. Because many stress pathway factors that are activated in meiosis are downstream of Ndt80 expression, we believe that they may hold the key to meiotic rejuvenation.