ConflictResolution
Financiado
Transcription replication conflicts in disease and development
Genetic and epigenetic instability contribute to cancers, aging, developmental disorders, and neurological diseases, so in-depth understanding how this instability arises is an important question affecting millions in Europe. Phys...
Genetic and epigenetic instability contribute to cancers, aging, developmental disorders, and neurological diseases, so in-depth understanding how this instability arises is an important question affecting millions in Europe. Physical conflicts between the transcription and DNA replication machineries are a potent endogenous source of this instability.
My preliminary data indicate that a single collision can trigger long-term epigenetic changes and affect the normal expression state of genes. I hypothesize that collisions can rewire gene expression networks and lead to cellular transformations relevant to disease and development. Unfortunately, this mechanism is largely understudied owing to the lack of suitable cellular systems to characterize collisions in molecular detail. My proposal will address this key gap in knowledge.
I recently pioneered a unique human cell-based episomal system to analyse collisions in an inducible and localized fashion. Using this highly tractable system, we will molecularly characterize the (epi)genetic consequences and identify novel factors that prevent or resolve collisions (Aim 1).
To address the relevance of collisions in disease, we will establish a novel proximity-labelling system (Split-APEX2) to map collision sites and identify their associated genetic and chromatin changes in a breast cancer cell model. This cutting-edge technology will decipher their role in pathological transformations observed in breast cancer genomes (Aim 2).
To link collisions to developmental transformations, we will determine their potential to induce local epigenetic changes during zygotic genome activation in mouse embryonic cells. This approach can shift the paradigm how cells in development first start to differ from each other and reprogram their genome into different cell types (Aim 3).
Uncovering the key principles of collisions may implement highly innovative approaches to avoid or establish cellular transformations in disease and development.
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Duración del proyecto: 73 meses
Fecha Inicio: 2019-10-25
Fecha Fin: 2025-11-30
Fecha Fin: 2025-11-30
Línea de financiación: concedida
El organismo H2020 notifico la concesión del proyecto el día 2019-10-25
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-2019-STG:
ERC Starting Grant
Cerrada
hace 6 años
Presupuesto
El presupuesto total del proyecto asciende a
1M€
Líder del proyecto
HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUN...
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Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5
4.61M€ |
Participante