Current Research and Scholarly Interests
My laboratory’s goal is to understand how cell growth triggers cell division. Linking growth to division is important because it allows cells to maintain a specific size range to best perform their physiological functions. Today, thanks to decades of research, we have an extensive, likely nearly complete parts-list of key regulatory proteins. Deletion, inhibition, or over-expression of these proteins often results in changes to cell size. However, the underlying molecular mechanisms for how growth triggers division are not understood. How do the regulatory proteins work together to produce a biochemical activity reflecting cell size or growth? Since we now have most of the parts, the next step to solving this fundamental question is to better understand how they work together.
My laboratory recently made a breakthrough discovery in understanding how growth triggers division in budding yeast. While it was expected that growth would act to increase the activities of the cyclin-dependent kinases (Cdk) known to promote cell division, this is not the case. Rather, we found that cell growth acts in the opposite manner. Cell growth triggers division by diluting a protein that inhibits cell division. We recently discovered an analogous mechanism operating in human cells.
Our discovery of a mechanism linking cell growth to cell division in budding yeast opens many avenues of research, three of which we are currently pursuing:
1. Cell size control results from the dilution of the cell cycle inhibitor Whi5 because its synthesis is independent of cell size. In contrast, most proteins are produced in proportion to cell size. We identified the set of proteins whose expression is largely independent of cell size. We now aim to determine the molecular mechanism(s) through which this occurs and identify the biological processes impacted.
2. We are addressing how gene expression depends on cell size in human cells. We are working with the Chan Zuckerberg Biohub Cell Atlas Project to establish a workflow so that all their single cell sequencing experiments will include data on cell size. This will allow us to examine cell size dependency of gene expression across an unprecedented number of human cell types.
3. Our work in yeast led us to the hypothesis that cell growth could trigger division in human cells by diluting a cell cycle inhibitor. We can apply our quantitative single-cell imaging approach because CRISPR-based genome editing allows us to tag cell cycle regulators with fluorescent proteins at their endogenous loci. We are now measuring and manipulating concentration dynamics in live cells to determine how cell growth impacts key regulators of division.
Our work has fundamental implications for understanding how the most basic aspect of cell morphology, cell size, is controlled. In the next 5 years, we aim to determine how growth triggers division in human cells, which has the potential to revolutionize our understanding of how cell division is regulated in both natural developmental contexts and in disease. Over the 5-10 year time horizon, we intend to pursue both developmental and medical directions.
