Weizmann Institute of Science, Rehovot, Israel
A computational biologist looks at how identical cells come to differ.
My main interest is in understanding how complex biological behaviours are encoded by DNA. An example of such behaviour is the ability of genetically identical cells to generate diversity in their phenotypes, or observable traits, by changing how genes are expressed from one cell to the next. How expression variability occurs over short timescales (for example, during a cell cycle) has been well studied; much less is known about it over longer timescales.
So I was excited by work from Narendra Maheshri of the Massachusetts Institute of Technology in Cambridge and his colleagues. They demonstrate that slow expression fluctuations of a yeast gene are regulated locally, or in cis, by that gene’s promoter — a nearby stretch of DNA that regulates the gene’s expression (L. M. Octavio et al. PLoS Genet. 5, e1000673; 2009).
They studied the yeast protein FLO11, placing two copies of the protein’s promoter in the same cell, each in front of an engineered fluorescent ‘reporter’ gene. The reporters switched expression slowly and independently, implying that the expression fluctuations were locally encoded. The authors further identified global, or trans, regulators that affect the fast and slow expression fluctuations of FLO11. The type of expression effect that a regulator exerts seems to depend on several factors, including the location of the regulator relative to the site at which transcription, or reading of the DNA, begins, and relative to sites for other regulators.
Although the mechanistic details of this encoding are still unclear, applying similar approaches to many more promoters should bring us closer to understanding how other complex phenomena are encoded by DNA. This will hopefully allow us to one day predict the phenotypic effects of human genetic variation.