Project 451055

A human body is composed of a multitude of cell types that are organized into tissues, organs, and physiological systems. The genome, composed of DNA, is the blueprint for all cells. Different types of cells can be made from the same blueprint because each cell type only uses parts of the genome. Thus, a central challenge in forming and maintaining different types of cells is how to keep some parts of the genome active, and others inactive. Polycomb proteins were discovered more than 50 years ago in fruit flies, where they keep parts of the genome that should not be used inactive in specific cells. Subsequently, Polycomb proteins were found to serve the same function in human cells. Indeed, Polycomb proteins are important for formation of different cell types in many parts of the body, including the brain, the blood and the immune system. Malfunction of Polycomb proteins can cause cells to read parts of the genome that are supposed to be inactive. This is implicated in several cancers and linked to Alzheimer's Disease. The molecular function of Polycomb proteins is to organize chromatin. Chromatin consists of the genome (DNA), and proteins that package it. Different parts of the genome are packaged in different forms. Active parts of the genome are organized for easy access so cells can read and use the information in the DNA, while inactive parts are tightly folded so that the DNA information is hidden. Polycomb proteins keep inactive parts of the genome quiet by folding them up tightly, but we do not know how they do this at a molecular level. Recently, a process called phase separation, the same process by which oil drops form in water, has been identified as important for organizing molecules in cells. Thus, collections of molecules that function together can form concentrated drops in cells that may function as molecular factories. We are testing whether Polycomb proteins might use phase separation to form drops that keep parts of the genome inactive.