Grant: Operating Grant

Polycomb Group (PcG) genes were discovered in fruit flies in the 1940s. They fascinated biologists because they help cells "remember" what kind of cell they are. Without PcG genes, cells forget their identities and fail to form all of the body structures. PcG genes were subsequently discovered in mammals for a completely different function-- the ability to promote tumours. Later it was found that, like in the fly, PcG genes are important for development of many body systems, including blood, the brain and the immune system. However, many additional studies also verified that PcG genes are involved in several different cancers. Thus, how cells remember who they are and how cells become cancerous are related processes. Molecular studies of the proteins made by PcG genes revealed that they regulate chromatin. Chromatin refers to the genetic material (DNA) when it is packaged with special proteins to organize it. All cells contain the same DNA, but their chromatin organization is different. Different cell types use only part of the DNA, that is, only some of their genes. Chromatin organizes the DNA so that genes that are used are easier to access, while those that are not needed are packaged more tightly. PcG proteins help maintain this organization. Cancer cells have altered cell identities and abnormal chromatin organization. Inappropriate behavior of PcG proteins contributes to this change in organization. When cells divide, the way that DNA is copied disrupts chromatin packaging. PcG proteins help cells remember how the chromatin is packaged so that the correct organization can be put back in place as soon as the DNA is copied. Our work aims to understand how this can occur. We use an approach termed "biochemical reconstitution" in which we recreate the behavior of chromatin and PcG proteins during copying of DNA in test tubes. Understanding how PcG proteins remember chromatin packaging will help us understand how and why chromatin is disrupted in cancer.