When it comes to gene regulation, there are more similarities between fruit flies and humans than previously thought, according to new Northwestern Medicine research published in Molecular Cell.
“In flies, the decision to turn a gene off can be locked in place by factors called Polycomb-group proteins; however, this locking mechanism can be counteracted by a protein called Trithorax (trx) to keep the gene on,” explained Ryan Rickels, first author of the paper and a PhD student in Feinberg’s Driskill Graduate Program (DGP). “We found many similarities between flies and humans regarding how these two opposing protein complexes strike a balance to keep a gene either on or off.”
Rickels conducted the research in the lab of senior author Ali Shilatifard, PhD, the Robert Francis Furchgott Professor and chair of Biochemistry and Molecular Genetics. Shilatifard and postdoctoral fellow Andrea Piunti, PhD, recently wrote a review in the journal Science that described research to date on the Polycomb and Trithorax protein families and their role in cancer development.
“We were curious to learn more about trx because its human homolog, MLL1, is highly mutated in several aggressive leukemias,” Rickels said. “By taking what we learned in flies and applying it to human cells, we were able to identify a set of genes which remain balanced by the actions of MLL1 and Polycomb.”
The set of balanced genes will likely differ from one type of cell to another – in this study, the scientists used human colon cancer cells – but the findings may help investigators predict which genes are balanced in different tissues.
While the study showed that MLL1 proteins are necessary to block repression by Polycomb proteins, exactly how MLL1 accomplishes the task is still unknown.
“My next set of experiments will determine whether or not MLL1’s enzymatic activity is necessary to block Polycomb,” Rickels said. “If it is not found to be essential, then I will whittle away at the protein until resolving which portion of MLL1 is necessary for maintaining the balance.”
The ultimate goal of this research?
“We hope to better understand the molecular mechanisms guiding these processes, which will increase our comprehension of how various MLL1 mutations result in aggressive cancers,” Rickels said.
Principal investigator Shilatifard is a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Studies on Drosophila Trx and mammalian MLL1 in his lab were supported in part by a grant from the National Institutes of Health R35CA197569.