Grant: Project Grant

DNA contains the molecular instructions for all processes required for life. The "central dogma" of molecular biology is this information is decoded by being copied ("transcribed") into RNA and then converted ("translated") into proteins, the key building blocks of the cell. Transcription is the process by which the DNA is copied ("transcribed") into RNA. In different cell types, at different times in development, and in response to different cues, information from different genes (segments of DNA) is needed, and thus must be transcribed into RNA. This is achieved by transcription regulation-the process by which RNA polymerases select which DNA segments to copy and how many copies to make. RNA polymerases are controlled by bringing them to the starting point of the selected DNA segment, and regulating how often they start copying, and how fast they work. Transcription regulation is essential for development and for cells to function. Many diseases are caused by disrupted transcription regulation, which also contributes to symptoms of most diseases. We are interested in transcription regulation that is carried out by a set of proteins called "Polycomb" proteins. These proteins were discovered in fruit flies, but we now know they are also present and essential in humans. Polycomb proteins repress transcription-preventing specific genes from being copied into RNA. Despite the importance of this process, we don't know exactly how the Polycomb proteins prevent RNA polymerase from copying certain DNA segments. In our proposal, we aim to determine how Polycomb proteins prevent transcription by combining high-resolution methods to observe what the Polycomb proteins are doing at the molecular level. Do they block access of RNA polymerase to certain DNA segments? Or slow it down or cause it to quit partway through a copy? Understanding these mechanisms may help explain how Polycomb proteins contribute to disease and provide new ideas for therapeutic approaches.