Biology subjects

Brent, R.

Publications and source records attributed to Brent, R..

3 recordsLinked to original sources

bioRxiv2018

Differences in protein dosage underlie nongenetic differences in traits

Phenotypic expression of many traits varies among isogenic individuals in homogeneous environments. Intrinsic variation in the protein chaperone system affects a wide variety of traits in diverse biological systems. In C. elegans, expression of hsp-16.2 chaperone biomarkers predicts the penetrance of mutations and lifespan after heat shock. But the physiological mechanisms by which cells express different amounts of the biomarker were unknown. Here, we used an in vivo microscopy approach to dissect the mechanisms of cell-to-cell variation in hsp-16.2 biomarker expression, focusing on the intestines, which generate most signal. We found both intrinsic noise and signaling noise are low. The major axis of cell-to-cell variation in gene expression is composed of general differences in protein dosage. Thus, hsp-16.2 biomarkers reveal states of high or low effective dosages for many genes. It is possible that natural variation in protein dosage or chaperone activity may account for missing heritability of some traits.

systems biology↗

bioRxiv2016

Cell-to-cell variability in the yeast pheromone response: high throughput screen identifiesgenes with different effects on transmitted signal and response

Populations of isogenic cells often respond coherently to signals despite differences in protein abundance and cell state. Our previous work in the Saccharomyces cerevisiae pheromone response system (PRS) uncovered processes that reduced cell-to-cell variation in signal and response. To understand these and other processes that controlled variation, we generated a whole-genome collection of haploid strains with deletions in non-essential genes and used high-throughput flow cytometry to screen more than 1000. We identified 50 \"variation genes\" required for normal cell-to-cell variability in signal and response. Some genes affected only signal variability, signal strength, or system output, defining these quantities as separable \"axes\" of system behavior. Two genes affected cytoplasmic microtubule function.

systems biology↗

bioRxiv2016

Cell-to-cell variability in the yeast pheromone response: Cytoplasmic microtubule functionstabilizes signal generation and promotes accurate fate choice

In a companion paper, we carried out a high-throughput screen to identify genes that suppressed cell-to-cell variability in signaling in yeast. Two genes affected cytoplasmic microtubules that can connect the nucleus to a signaling site on the membrane. Here, we show that microtubule perturbations that affected polymerization and depolymerization, membrane attachment, and force generation increased variability. For some perturbations, \"outlier\" cells drove the increased variability. Bypass experiments that activated the PRS ectopically at downstream points indicated that microtubule-dependent processes might stabilize the membrane-recruited scaffold protein Ste5. The variability caused by microtubule perturbations required the MAP kinase Fus3. Microtubule perturbations hindered stable scaffold formation and decreased the accuracy of a polarity-dependent fate choice. Our experiments suggest that membrane-attached microtubules stabilize signaling by scaffold-bound Fus3, and are consistent with a model in which signaling irregularities from changes in microtubule function are amplified by cross-stimulatory feedbacks among PRS proteins. The fact that microtubule perturbations also cause aberrant fate and polarity decisions during embryonic development and cancer initiation suggests that similar variation-reducing processes might also operate in metazoans.

systems biology↗