Phenotypic Heterogeneity & Persistence
Phenotypic persisters are individual microbes that survive harsh treatments that kill the majority of their genetically identical sister cells. Persistence has been described in many bacterial species, and was recently implicated in the ability of individual cancer cells to survive chemotherapy. Revealing the stochastic event triggering persistence is a major challenge to eradicating this subpopulation. Although persisters were discovered many decades ago, the stochastic event triggering persistence is poorly understood. We are trying to understand phenomenon of phenotypic heterogeneity and persistence in budding yeast, and its underlying molecular mechanism.
Coupling phenotypic persistence to DNA damage increases genetic diversity in severe stress, Nature Ecology & Evolution (2017)
DNA Replication & Chromatin
Eukaryotic cells initiate DNA synthesis by sequential firing of hundreds of origins. We are trying to understand the regulation of DNA replication. In one line of study, we devised a model that enables studying replication dynamics that are deduced from replication profiles of free-cycling cells. In a different project, we study the interplay between DNA replication and chromatin. In eukaryotic cells, DNA is wrapped around histone octamers to form nucleosomes, the basic building blocks of the chromatin structure. This packing presents a unified platform for regulating processes that require DNA accessibility. We also try to understand how expression homeostasis is maintained during DNA replication, despite changes in DNA dosage.
Model-based analysis of DNA replication profiles: Predicting replication fork velocity and initiation rate by profiling free-cycling cells, Genome Research (2016)
Chromatin dynamics during DNA replication, Genome Research (2016)
Expression Homeostasis during DNA replication, Science (2016)
The merging of genomes in inter-specific hybrids can result in novel phenotypes, including increased growth rate and biomass yield, a phenomenon known as heterosis. We describe a budding yeast hybrid that grows faster than its parents under different environments. Phenotypically, the hybrid progresses more rapidly through cell cycle checkpoints, relieves the repression of respiration in fast growing conditions, does not slow down its growth when presented with ethanol stress, and shows increasing signs of DNA damage. A systematic genetic screen identified hundreds of alleles affecting hybrid growth whose identity vastly differed between the hybrid and its parent and between growth conditions. This large-scale rewiring of allele effects suggests that despite showing clear heterosis, the hybrid is perturbed in multiple regulatory processes. We discuss the possibility that incompatibilities contribute to hybrid vigor by perturbing safeguard mechanisms that limit growth in the parental background.
Large-scale rewiring in a yeast hybrid, biorXiv (2016)
Morphogen gradients & Scaling
Morphogen gradients guide the patterning of tissues and organs during the development of multicellular organisms. In many cases, morphogen signaling is also required for tissue growth. The consequences of this interplay between growth and patterning are not well understood. In collaboration with Professor Benny Shilo (WIS), we try understand this phenomenon using both mathemtical models and experimental tools.
A WntD-Dependent Integral Feedback Loop Attenuates Variability in Drosophila Toll Signaling., Developmental Cell (2016)
Periodic patterning of the Drosophila eye is stabilized by the diffusible activator Scabrous., Nature Communications (2016)
Cell Size Control
Growing cells adjust their division time with biomass accumulation to maintain growth homeostasis. Size control mechanisms, such as the size checkpoint, provide an inherent coupling of growth and division by gating certain cell cycle transitions based on cell size. We use genetic manipulations and live microscopy of individual cells growing to study this regulation.
Loss of growth homeostasis by genetic decoupling of cell division from biomass growth: implication for size control mechanisms., Molecular Systems Biology (2014)