In a recent review published in the journal Science, Northwestern Medicine scientists explored research that has shown how the balanced activities of two protein families – Polycomb and Trithorax – regulate gene expression during embryonic development.
When mutations knock the activity of these proteins out of balance, diseases such as cancer form. Polycomb and Trithorax are therefore significant areas of interest in the field of epigenetics and chromatin biology, which studies the mechanisms that govern gene expression.
“A balanced state of gene expression plays a central role in disease pathogenesis,” said Ali Shilatifard, PhD, the Robert Francis Furchgott Professor and chair of Biochemistry and Molecular Genetics and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. He wrote the review with Andrea Piunti, PhD, a postdoctoral fellow in his lab.
Proteins within the Polycomb and Trithorax complexes are chromatin modifiers. This means they’re responsible for changing the structure of DNA to control gene expression, or transcription, the process in which genetic information from DNA is copied and used to produce proteins.
“This story started over 40 years ago, when geneticists identified the two gene families in Drosophila melanogaster. The Polycomb family was thought to be the brakes in the process of development. Trithorax was considered the gas pedal,” Shilatifard explained. “Then, about 20 years ago, biochemists started purifying some of the gene products within these complexes and identifying their biochemical activities.”
Shilatifard’s lab was the first to biochemically purify and identify Trithorax within the COMPASS family as a histone H3 Lysine 4 methylase. Meanwhile, scientists sequencing cancer genomes found mutations in the Polycomb and COMPASS complexes in a myriad of cancers, including both solid tumors and blood malignancies, as well as developmental disorders.
“Now, as a community, we’re trying to figure out how we can take advantage of information about these mutations and the activity of these complexes to develop targeted therapeutics for cancer,” Piunti said.
In the new review, Shilatifard and Piunti detailed the latest scientific advances related to the Polycomb and COMPASS complexes and discussed the ways those findings can translate to the treatment of human disease.