AMBITION · Unravelling the molecular Basis of epigenetic silencing: what factors define a gene as a Polycomb target?

Unravelling the molecular Basis of epigenetic silencing: what factors define a gene as a Polycomb target?

Establishment and maintenance of gene expression states is central to development and differentiation in any eukaryotic organism. An important component of maintenance of developmentally specified gene expression is gene silencing mediated by Polycomb group (PcG) proteins. Polycomb group proteins are conserved from vertebrates to plants and are associated with at least two chromatin-modifying complexes: Polycomb repressive complex 1 and 2 (PRC1, PRC2), which establish transcriptional silencing of target genes. Polycomb regulation maintains correct gene expression states throughout development and perturbations lead to developmental abnormalities and disease. Knowledge about the composition of individual PRC complexes and their biochemical modes of action has advanced in the recent years. However, one of the central questions in the field of chromatin biology remains unanswered: which factors specify a gene for Polycomb silencing? An ideal system to study Polycomb targeting is a locus where epigenetic silencing can be induced externally, and the maintenance of silencing can be easily recorded during subsequent development. In the model plant Arabidopsis thaliana, the integration of complex developmental and environmental signals determining flowering time occurs via tight regulation of the floral repressor gene FLOWERING LOCUS C (FLC). At FLC, specific DNA binding proteins (VAL1, VAL2) and their partners interact in a not yet fully understood regulatory network with Polycomb proteins, which consequently converts environmental cues (prolonged cold) into stable epigenetic memory (silencing of the gene). Building on previously identified proteomic interactions, the AMBITION project hypothesised that FLC regulation involves components of the Apoptosis and Splicing Associated Protein (ASAP) complex. ASAP functions in RNA processing and quality control, thus putatively linking VAL1 DNA sequence specificity with co-transcriptional regulation directly to Polycomb mediated epigenetic silencing. The project combined several interconnected molecular, biochemical and genetic avenues to provide novel and detailed mechanistic insights into the epigenetic regulation of Polycomb target genes.

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