CORDIS
EU research results

CORDIS

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Transcription-replication conflicts in disease and development

Project information

Grant agreement ID: 852798

Status

Grant agreement signed

  • Start date

    1 February 2020

  • End date

    31 January 2025

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 1 497 530

  • EU contribution

    € 1 497 530

Hosted by:

HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH

Germany

Objective

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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Host institution

HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH

Address

Ingolstadter Landstrasse 1
85764 Neuherberg

Germany

Activity type

Research Organisations

EU Contribution

€ 1 497 530

Beneficiaries (1)

HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH

Germany

EU Contribution

€ 1 497 530

Project information

Grant agreement ID: 852798

Status

Grant agreement signed

  • Start date

    1 February 2020

  • End date

    31 January 2025

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 1 497 530

  • EU contribution

    € 1 497 530

Hosted by:

HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH

Germany