Single Molecule Dynamics of Differentiation
By allowing us to see the unseen world, microscopy has profoundly shaped our scientific endeavors. My lab is developing new tools to push the envelope of microscopy in living cells. One key question we would like to answer is: how are different genes activated as cells differentiate into specialized cell types, and can we utilize advanced microscopy technology to visualize and better understand the dynamic, coordinated processes involved?
Cell differentiation, whereby a functionally specialized cell arises from a multipotent precursor cell, underlies the development of multicellular life. This process occurs by the coordinated expression of hundreds of target genes that together reprogram an undifferentiated stem cell into a functionally specialized cell. We now know that this gene expression is controlled not only by the concentrations of key transcription factors, which bind to specific regions of DNA to turn genes on or off, but also via alterations to the structure and accessibility of their target sites in the DNA. Intriguingly, this process can be regulated both by biochemical (soluble growth factors and hormones) as well as biophysical (physical interactions with the surrounding environment) factors. As both are dysregulated in developmental disorders and in diseases like cancer, understanding how these seemingly disparate factors coordinate to determine cell identity is an open question with major implications for human health.
We are using our new technologies to directly visualize how key transcription factors search for, identify, and turn on target genes in the nucleus of differentiating cells. By using changes in the kinetics of these molecules as a read-out for nuclear structure, we are exploring how biochemical and biophysical factors regulate nuclear organization, DNA accessibility, and gene expression to control cellular fate. Answers to this question would provide new insight not only into how these factors drive normal development, but also how their dysregulation may be targeted in a wide range of human diseases.