Gene regulation allows cells to respond to internal and external stimuli and signals. Specifically, a certain trigger activates one or several molecular cascades that ultimately lead to an adaptation of the expression levels of certain genes. Naïvely, such regulation should always yield a similar response to a given signal, unless changes in the organism’s genetic information generate differences in the regulatory circuit.
However, this naïve view on gene regulation is now being challenged because recent observations suggest that a very rudimentary form of “memory” (i.e. the ability to store information about past experiences and use this information to adapt later behavior) may be rooted in regulatory circuits that exist even in relatively simple life forms like single-celled microbes. Advances in epigenetics have uncovered mechanisms that allow semi-stable non-genetic adaptations in the way that the genes of an organism are regulated. Moreover, recent developments in single-cell analyses have uncovered numerous examples of how genetically identical cells in the same environment do not always show the same response, and how a cell’s response often depend on its history (referred to as “hysteresis”, a technical term that indicates that a system’s response depends on previous inputs or states). Specifically, microbes can adapt their response to a stimulus depending on past experiences, such as nutrients that were once available or stresses that were once present. Such history-dependent behavior might allow cells to prepare for future events that they have "learned" over evolutionary timescales to always expect after a priming event.
The traditional view of static and deterministic regulation is therefore gradually replaced by models with an important role for stochasticity (random or only partly regulated events) and hysteresis. Whereas the number of studies that report hysteresis steadily increasing, relatively little is known about the underlying mechanisms.
One the best-studied example of gene regulation is the regulation of switches between carbon sources in the budding yeast, Saccharomyces cerevisiae. When confronted with a mixture of different sugars, yeast cells first utilize glucose, before activating genes necessary for the consumption of non-preferred sugars like galactose or maltose (a phenomenon known as “catabolite repression”). The switch from glucose to non-preferred sugars takes some time (the so-called “lag phase”) during which the cells stop consuming sugars and stop growing until they have activated the genes necessary to start the consumption of the alternative sugar. Interestingly, exposing yeast to maltose or galactose, then glucose, and then again maltose or galactose, reduces the average lag time. This implies that this regulation shows some form of “memory” or hysteresis.
OBJECTIVES AND SPECIFIC AIMS
Strategic objective
We propose a multidisciplinary approach to obtain a comprehensive view of the different genes and mechanisms that contribute to history-dependent behavior, and study its biological relevance.
To reach our goals, we will use the S. cerevisiae MAL circuit as a new model for hysteresis in gene regulation.
Specific scientific aims:
1. To provide a comprehensive description and quantitative analysis of hysteresis in MAL regulation (WP1)
2. To unravel the molecular mechanisms and genes contributing to hysteresis (WP2 and WP3)
3. To unravel the epigenetic mechanisms that allow hysteresis to extend over several generations (WP4)
4. To characterize the ecological relevance of hysteresis (WP5).
Specific Technological aims:
1. Development of new microfluidics devices that allow studying individual cell responses
2. Adaptation of the Chip-Exo technology to study nucleosome positioning using Illumina sequencing
3. Employ our knowledge to obtain superior industrial yeast variants with faster fermentation performance
