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ANR funded project

Une nouvelle représentation du vivant (DS0401) 2014
Projet ORICHOICE

Replication origins choice in the control of genomic stability and cell identity

At each cell division, DNA replication allows the faithful transmission to daughter cells of the genomic information contained in our chromosomes. It is an active process during embryonic development, that also permits the renewal of millions of cells each second in adult life. Errors in this process lead to genome instability and developmental failure or disease. Initiation of DNA replication at replication origins is the focus of this project.
Paradoxically, initiation of DNA replication during the cell cycle, a major cell function, remains poorly understood in metazoans and deciphering its rules is a key challenge. In human cells, there are 50 000 to 100 000 DNA replication origins along chromosomes from which DNA synthesis is initiated. They have started to be characterized at the genome-wide scale, but their nature remains elusive. Nevertheless, it is increasingly acknowledged that their organization along DNA is crucial for programming eukaryotic chromosomes. Several years ago, we hypothesized that DNA replication origins are structural elements of our genome that contribute to tissue-specific gene expression during development. We believe that a differential encoding of chromosomes by DNA replication origins is instrumental in cell identity acquisition during development and differentiation. Defects in the usage of DNA replication origins that result in under- or over-replication, may promote genomic instability, including chromosomal re-arrangements that lead to ageing and genetic diseases.
Using new procedures to map DNA replication origins genome-wide, we recently identified and characterized replication origins in mouse pluripotent stem cells (chromosome 11) and in Drosophila cells (whole genome). We have since extended these results to the whole mouse genome by high-throughput DNA sequencing (to be submitted). Although replication origins are at defined positions in the genome, our data confirm that only a portion is used at each cell cycle in a given cell. This plasticity in replication origin usage is not well understood. In this project, we wish to address whether DNA replication origin signatures along chromosomes influence cell fate and contribute to cell identity during the differentiation of pluripotent cells. We plan to determine whether their positioning influences the organization of chromatin domains that may in turn affect transcriptional programs during differentiation. We will also identify and characterize small non-coding nuclear RNAs as new epigenetic signatures involved in the regulation, positioning and activity of replication origins.
The links between DNA replication origins and cell fate will be addressed using well-defined mouse and human differentiating cell models.
The main question is whether replication origin-positioning signatures correlate with and influence cell fate during development. This will be addressed using two biological systems. In the first objective, we will analyze changes in origin position following the induction of neural precursors from mouse embryonic stem cells as a model system. In the second objective, we will analyze origin distribution during expansion and differentiation of human and murine hematopoietic stem cells and also in human embryonic stem cells. The third objective is to unravel the role of small nuclear non-coding RNA signatures in the choice and control of the replication origins to be activated.
The expertise necessary to achieve the objectives of this project is impossible to find in a single group. The consortium gathers teams from three different units that have precise tasks in the project: expertise in murine and human ES cells, in mapping DNA replication origins and methods for DNA replication (Méchali’s group); expertise in murine and human hematopoietic cell maintenance and differentiation and their genetic modifications (Taylor’s group); and expertise in genome bioinformatics and computational biology (van Helden’s group).

Partners

IGH INSTITUT DE GENETIQUE HUMAINE UPR1142 CNRS

IGMM INSTITUT DE GENETIQUE MOLECULAIRE DE MONTPELLIER, UMR5535

TAGC TAGC INSERM U1090

ANR grant: 549 965 euros
Beginning and duration: octobre 2014 - 36 mois

 

ANR Programme: Une nouvelle représentation du vivant (DS0401) 2014

Project ID: ANR-14-CE10-0019

Project coordinator:
Monsieur Marcel Méchali (INSTITUT DE GENETIQUE HUMAINE UPR1142 CNRS)

 

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The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.