Descripción del proyecto
La investigación podría desvelar cómo las proteínas del grupo Polycomb fomentan el cambio epigenético
La regulación epigenética de la expresión génica mediante las proteínas del grupo Polycomb es fundamental para el desarrollo y la plasticidad ambiental de muchas eucariotas. PRC2, una clase de proteínas del grupo Polycomb, puede silenciar los sitios genómicos conocidos como regiones de nucleación o elementos de respuesta Polycomb. El proyecto EPISWITCH, financiado con fondos europeos, utilizará un sistema genético bien caracterizado, Arabidopsis FLC, para dilucidar los mecanismos básicos del cambio epigenético que aplica esta familia de complejos proteicos. Este proyecto interdisciplinario determinará las características locales de la cromatina que fomenta el cambio epigenético independientemente en cada alelo. También describirá cómo la replicación del ADN afecta a la transición del silenciamiento epigenético de metaestable a largo plazo.
Objetivo
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.
Ámbito científico
- natural sciencesbiological sciencesmolecular biologymolecular genetics
- natural sciencesbiological sciencesgeneticsDNA
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencesgeneticsepigenetics
- natural sciencesbiological sciencesmolecular biologystructural biology
Palabras clave
Programa(s)
Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
NR4 7UH Norwich
Reino Unido