Epigenetic regulation by Polycomb-Trithorax system: leaving the mark on histones and other proteins
is financed by the Swedish Research Council.
We investigate the mechanisms of two protein groups that control gene expression: Polycomb and Trithorax. If we can understand and control this epigenetic regulatory system, which is present in all multicellular organisms, we can promote the development of individualized medicine and stem cell therapies.
That our DNA decides who we are is an accepted truth, but all our cells have the same information—the same genome—and still they have different functions. Their differences do not lie in the genetic information itself, but in how it is used, which is controlled by the epigenome. The ability of cells to have different epigenomes is a requirement for multicellular organisms. The cell senses which genes should be used, and this information is inherited when the cell divides, so that the cell knows what tissue it belongs to. This is called the epigenetic memory, as it is inherited separately from the DNA sequence.
Our project focuses on the epigenetic control system that all multicellular organisms have: gene regulation by Polycomb and Trithorax proteins. Polycomb proteins keep hundreds of developmental genes shut off, and therefore controls cell differentiation and tissue homeostasis. Trithorax counteracts Polycomb and makes sure it does not shut off genes in cells where they should be used.
When Polycomb proteins repress genes they methylate histones, the proteins that DNA is wrapped around. The methylation works as a covalent mark that makes sure both copies of the gene is repressed after DNA replication. Trithorax proteins also methylate histones, but this methylation is not necessary to counteract Polycomb, which implies other, novel substrates.
Why does histone methylation facilitate Polycomb repression? Which substrate does Trithorax methylate to counteract Polycomb? To answer these questions we will perform experiments in fruit flies and human cells, with a mix of genetic and biochemical techniques and advanced numerical modelling.
The continued development of therapies such as individualized medicine and stem cell therapy depends on our understanding of gene expression programs and our ability to modify these programs in ways that are stable over several cell generations. Our goal is to help the development of these therapies by mapping the basic mechanisms of the epigenetic memory.