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Our lab is interested in the systems biology and evolution of epigenetic switches (bistability) and clocks (oscillators) in gene regulatory networks. We use experiment and theory, biology and physics, systems and synthetic biology to study the cell cycle, metabolic rhythms, and circadian clocks. How do oscillators with different frequencies co-exist in the same cell? Are there mechanisms and regulatory principles that ensure functional harmony between oscillators?

Genome of giant amoeba reveals evolutionary secrets

Physarum polycephalumPhysarum polycephalum (“many-headed slime”) is a giant amoeba with similarities to the common ancestor of amoeba, fungi and animals. Our lab helped analyze its genome to show that it has molecular features that were once thought to be specific for either animals or plants. Like animals (but unlike plants or fungi), Physarum uses tyrosine-kinase signaling for processing. Nick Buchler analyzed cell cycle regulators in Physarum and other amoeboid genomes to show that Physarum may be a better model organism than yeast and fungi for studying conserved mechanisms of cell cycle regulation in the ancestor of amoeba and animals.

Schaap P et al, The Physarum polycephalum genome reveals extensive use of prokaryotic two-component and metazoan-type tyrosine kinase signaling. Genome Biol Evol. 8: 109 (2016)

Circular logic of the yeast metabolic cycle and cell division cycle

Screen Shot 2015-12-30 at 10.27.35 AMWe studied the interaction of two oscillators, the cell division cycle (CDC) and yeast metabolic cycle (YMC) in budding yeast. Previous work suggested that these cycles interact to separate high oxygen consumption from DNA replication to prevent genetic damage. To test this hypothesis, Tony Burnetti grew genetically diverse strains at a number of growth rates and measured DNA replication and oxygen consumption with high temporal resolution. His data showed that high oxygen consumption is not strictly separated from DNA replication; rather, cell cycle Start was coupled with the initiation of high oxygen consumption and catabolism of storage carbohydrates. The function of this YMC-CDC coupling may be to ensure that DNA replication and cell division occur only when sufficient cellular energy reserves have accumulated. More generally, our approach shows how studies in genetically diverse strains efficiently identify robust phenotypes and steer the experimentalist away from strain-specific idiosyncrasies.

Burnetti AJ, Aydin M, Buchler NE. Cell cycle Start is coupled to entry into the yeast metabolic cycle across diverse strains and growth rates. Mol. Biol. Cell 27: 64 (2016)

Role of DNA binding sites and slow unbinding kinetics in titration-based oscillators

ATCIn theory, the unbinding rates of activators and repressors from DNA are presumed to be faster than gene expression. In practice, this assumption is not always true. Sargis Karapeytan analyzed two synthetic oscillators (activation-titration and repressor-titration) to understand the key parameters that are important for oscillations and for overcoming the molecular noise that arises from slow DNA unbinding.  Counter-intuitively, our biophysical modeling and stochastic simulations showed that slow values of DNA unbinding rate stabilized the oscillators. We also show that multiple binding sites increase the robustness of oscillations due to the buffering of DNA unbinding events. This work demonstrates how the number of DNA binding sites and slow unbinding kinetics, which are often omitted in biophysical models of gene circuits, have a significant impact on the dynamics of synthetic oscillators.

Karapetyan S, Buchler NE. Role of DNA binding sites and slow unbinding kinetics in titration-based oscillators. Phys. Rev. E 92: 062712 (2015)