Descripción del proyecto
Integridad de las modificaciones epigenéticas tras daños en el ADN
Las modificaciones químicas en el ADN y las proteínas histonas se conocen colectivamente como epigenoma y tienen un papel fundamental en la regulación de la expresión génica. Sin embargo, no está claro cómo las modificaciones epigenéticas cambian en respuesta a los daños en el ADN y cómo estas contribuyen a la respuesta de reparación. Para subsanar esta laguna de conocimiento, los científicos del proyecto REMIND, financiado con fondos europeos, analizarán las modificaciones de las histonas y el estado de metilación del ADN en los fragmentos de ADN en reparación en células humanas previamente sometidas a daños por rayos UVC. Esta información, combinada con la caracterización detallada de los agentes moleculares que contribuyen a la restauración de la cromatina, ayudará a diseccionar el mantenimiento y la herencia del epigenoma tras la reparación del ADN.
Objetivo
Cell viability and homeostasis rely on the stable maintenance of the epigenetic information conveyed by chromatin, which associates DNA and histone proteins in the cell nucleus and governs gene expression programs. Yet, epigenome integrity is challenged during all DNA transactions, including DNA damage repair. While much effort has been devoted to characterizing chromatin alterations in response to DNA damage and how they contribute to the repair response, our knowledge of this fundamental process is largely incomplete, and whether and how epigenetic features are re-established following a genotoxic stress challenge is still unexplored. Thus, a comprehensive framework of the mechanisms underlying the maintenance of epigenome integrity in response to DNA damage is lacking.
The present project aims to fill this important gap by profiling the epigenome of repair patches following UVC damage in human cells and by characterizing the molecular players contributing to chromatin restoration/plasticity. I propose an integrated approach that tackles this question at different levels of chromatin organization, from histone and DNA modifications up to higher-order chromatin folding.
Building on our unique expertise and through the development of powerful novel methodologies, combining cutting-edge imaging, proteomics and epigenomic technologies, we will elucidate mechanisms for (1) histone modification re-establishment and maintenance and (2) DNA methylation inheritance at repair sites. We will also investigate how repair-associated changes in DNA and histone modifications reflect at the level of (3) higher-order chromatin organization in the tridimensional nuclear space, and dissect (4) functional crosstalks between the epigenetic changes that arise in damaged chromatin. This ambitious research project represents an unprecedented effort towards a comprehensive and integrated understanding of epigenome maintenance mechanisms in response to genotoxic stress.
Ámbito científico
Palabras clave
Programa(s)
Régimen de financiación
ERC-COG - Consolidator GrantInstitución de acogida
75794 Paris
Francia