Descripción del proyecto
Histonas y replicación del ADN
Los fenómenos epigenéticos intervienen en la diferenciación celular durante el desarrollo, el desarrollo del cáncer y la susceptibilidad a las enfermedades. Aunque se sabe que la herencia de los componentes de la cromatina es un desencadenante de estos fenómenos, aún no se conoce del todo el papel de las histonas y su patrón hereditario. En el proyecto NChIP, financiado por el Consejo Europeo de Investigación, se estudiará cómo se mueven las histonas y los reguladores de la cromatina durante la replicación del ADN en la levadura. La intención es determinar cómo los estados de la cromatina soportan las alteraciones provocadas por la replicación del ADN. Los resultados contribuirán de forma considerable a comprender el proceso de constitución de la cromatina y su papel para mantener la integridad de la información genética.
Objetivo
Chromatin assembly is a fundamental cellular process necessary for the maintenance of genome integrity and transcriptional programs. Understanding the effect of DNA replication on histone protein dynamics is also a prerequisite for understanding the role of chromatin in epigenetic inheritance. Epigenetic phenomena are thought to influence cellular differentiation and cancer formation, as well as the impact of environmental factors on early development and later predispositions to disease. While epigenetic inheritance of chromatin components is, in theory, accepted as the driver of such phenomena, chromatin state inheritance per se has only been demonstrated for a few specific cases. Not much is known about histone “inheritance” beyond the facts that bulk maternal histones distribute equally among the daughter strands and are diluted two-fold after replication with newly synthesized “unmarked” histones, and that the majority of H3/H4 tetramers do not split before reassembly. We have shown previously that maternal nucleosomes stay on average within 400bp of their original binding site, implying that any potentially heritable chromatin encoded information, has to be inherited in ~1kb blocs, as smaller nucleosome domains would rapidly be diluted by new nucleosomes.
I propose to develop high throughput systems for directly measuring movements of histones and chromatin regulators during genomic replication in S.cerevisiae to determine, how chromatin states survive the perturbations associated with replication. We will determine locus specific differences in the spread of maternal nucleosomes after replication, the effects of leading and lagging strand replication on nucleosome positioning and maternal nucleosome distribution, the renewal dynamics of posttranslational histone marks and chromatin binding proteins, and the kinetics of chromatin footprint re-establishment and gene (re)activation.
Ámbito científico
Programa(s)
Régimen de financiación
ERC-COG - Consolidator GrantInstitución de acogida
75794 Paris
Francia