What We Do
Cheeseman Lab Research
The goal of our laboratory is to define the molecular mechanisms by which cells divide. To grow from a single cell to the 30 trillion cells in the human body, cells undergo a series of divisions. During each division, the genetic material must be equally partitioned to the daughter cells. To accomplish this, cells progress through multiple phases of the cell cycle, which coordinates the preparation and execution of cell division. Cell cycle defects, such as checkpoint failure or chromosome mis-segregation, can cause severe developmental consequences and disease.
Molecular mechanisms regulating cell division
Figure 1. Kinetochore assembly in mammalian cells.
Figure 2. Model of mitotic timing regulation by balance of Cdc20 translational isoform levels.
The prior work in the Cheeseman lab focused primarily on the fundamental mechanisms of chromosome segregation, specifically assembly of kinetochores – the macromolecular structure that connects microtubules to mitotic chromosomes. We continue to explore how post-translational modifications, protein degradation, and multivalent interactions control kinetochore assembly. In addition, our lab is investigating mitotic signaling pathways and how their dysregulation contributes to disease. Specifically, we are interested in how cells regulate mitotic timing by tuning the relative levels of translational isoforms of spindle assembly checkpoint proteins. For our ongoing work, we are particularly interested in understanding how these core cellular processes are rewired across diverse physiological contexts, including across the cell cycle and in different cell types and cell states, such as quiescence and senescence.
Large scale phenotypic screening
Figure 3. Large-scale optical screen reveals the phenotypic landscape of human essential genes.
As part of an ongoing collaboration with Paul Blainey’s lab at the Broad Institute, we seek to conduct cell biological studies at a large scale. We have optimized optical screening that combines CRISPR-based gene targeting with automated microscopy to define the morphological phenotypes of every essential gene knockout. Our lab aims to use this technology to systematically uncover the functions of understudied genes and place annotated genes in new cell biological pathways, including those related to cell division.
Control of gene expression during the cell cycle
Figure 4. Cell cycle progression requires regulation of gene expression on many levels
Temporal regulation of gene expression is required to coordinate rapid and complex cellular events, such as DNA replication during S phase or chromosome segregation during mitosis. Our lab is interested in transcriptional and post-transcriptional control of gene expression and its contribution to cell cycle progression. Using a combination of imaging, transcriptomics, ribosome profiling, and proteomics, we aim to understand the mechanisms that underlie broad changes in gene expression during the cell cycle.