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Mechanistic basis of nucleation and spreading underlying a Polycomb-mediated epigenetic switch

Project description

Research could uncover how polycomb-group proteins promote epigenetic switching

The epigenetic regulation of gene expression through polycomb-group proteins is central to the development and environmental plasticity of most eukaryotes. A class of polycomb-group proteins, PRC2 can epigenetically silence genomic sites known as nucleation regions or polycomb response elements. The EU-funded EPISWITCH project will use a well-characterised gene system, Arabidopsis FLC, to elucidate the core epigenetic switching mechanisms that this family of protein complexes puts into place. This interdisciplinary project will determine the local chromatin features that promote the epigenetic switch independently at each allele. It will also describe how DNA replication affects the transition from metastable to long-term epigenetic silencing.

Objective

Polycomb-mediated epigenetic regulation of gene expression is central to development and environmental plasticity in most eukaryotes. Polycomb Repressive Complex 2 (PRC2) is targeted to genomic sites, known as nucleation regions or Polycomb Response elements, and switches those targets to an epigenetically silenced state. But what constitutes the switching mechanism is unknown. Core epigenetic switching mechanisms have proven difficult to elucidate due to the complex molecular feedbacks involved. We will exploit a well-characterized gene system, Arabidopsis FLC, to address a central question – what are the core events that constitute a Polycomb switch?

Our hypothesis is that the epigenetic switch involves stochastic conformationally-induced oligomerization, generating an ordered protein assembly of PRC2 accessory proteins and PRC2, that is then robustly distributed onto both daughter strands during DNA replication through self-templating feedback mechanisms. We will determine the local chromatin features that promote the epigenetic switch independently at each allele (i.e. in cis). We will also dissect the involvement of DNA replication in the transition from metastable to long-term epigenetic silencing, associated with the Polycomb complex spreading across the body of the locus.

This interdisciplinary proposal combines molecular genetics/biology, computational biology, with structural biology, achieved through close working relationships with Prof. Martin Howard (John Innes Centre), Dr Mariann Bienz (MRC Laboratory of Molecular Biology, Cambridge) and Dr Julian Sale, (MRC Laboratory of Molecular Biology, Cambridge). This blue-sky programme aims to provide important new concepts in Polycomb-mediated epigenetic switching mechanisms, important for the whole epigenetics field.

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Coordinator

JOHN INNES CENTRE
Net EU contribution
€ 2 101 325,00
Address
Norwich research park colney
NR4 7UH Norwich
United Kingdom

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Region
East of England East Anglia Breckland and South Norfolk
Activity type
Research Organisations
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Other funding
€ 0,00

Beneficiaries (1)