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Transcription-replication conflicts in disease and development

Project description

Physical conflicts between DNA replication and transcription complexes

The polymerase complexes for DNA replication and transcription share the same template. Previous studies indicate that transcription polymerase complexes can arrest the progress of replication forks, leading to changes in gene expression and transmission. This EU-funded proposal focuses on these physical collisions at the molecular level. A novel inducible human cell-based episomal system will permit collision analysis to establish genetic consequences and factors that affect collisions. Investigation will also address the significance of collisions in disease initiation, mapping collision sites and defining associated genetic and chromatin changes in a breast cancer cell model as well as mouse embryonic cells. For novel therapies, the goal is to selectively avoid or establish cellular transformations.

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.

Host institution

HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH
Net EU contribution
€ 1 497 530,00
Address
INGOLSTADTER LANDSTRASSE 1
85764 Neuherberg
Germany

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Region
Bayern Oberbayern München, Landkreis
Activity type
Research Organisations
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Total cost
€ 1 497 530,00

Beneficiaries (1)