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

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

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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Host institution

JOHN INNES CENTRE

Address

Norwich Research Park Colney
Nr4 7uh Norwich

United Kingdom

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 2 101 325

Beneficiaries (1)

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JOHN INNES CENTRE

United Kingdom

EU Contribution

€ 2 101 325

Project information

Grant agreement ID: 833254

Status

Grant agreement signed

  • Start date

    1 September 2019

  • End date

    31 August 2024

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 2 101 325

  • EU contribution

    € 2 101 325

Hosted by:

JOHN INNES CENTRE

United Kingdom