Epigenetic regulation by the Polycomb-Trithorax system: leaving the mark on histones and other proteins

Designated master-regulatory genes control the development and homeostasis of a multicellular organism. Importantly, only a subset of these genes is active in any given cell type. The decision, which master-regulatory genes to block from being used, enables cell differentiation.

Such decisions are made at specific time points and then maintained by the epigenetic regulatory system comprised of Polycomb group proteins. To repress developmental genes, Polycomb group proteins must methylate histone H3 at Lysine 27.

This covalent modification serves as a molecular mark, which signals that both copies of a target gene should be repressed after DNA replication. Trithorax group proteins limit Polycomb repression. They also methylate histones.

However, this methylation is not required for anti-Polycomb function implying other, yet undiscovered, non-histone substrates. How is the histone methylation signal translated to facilitate Polycomb repression?

Which substrates do Trithorax group proteins methylate to counteract it?We propose a comprehensive program to address these challenging questions.

It includes transgenic experiments with cultured human cells, genetic and genomic experiments with fruit flies (Drosophila melanogaster) and advanced computational modelling.

By understanding how Polycomb and Trithorax systems work, we will further our knowledge of how cells keep their gene expression programs in check and thereby advance our ability to manipulate cell fates.