H2020Individual fellowship2017–2019

TeloChromatin · Dissecting the chromatin dynamics at telomeres during mouse pre-implantation development.

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration: 2017-07-01 → 2019-06-30
EU contribution: €173,076
Participants: 1
Scheme: MSCA-IF

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Results in brief

Dissecting the chromatin dynamics at telomeres during mouse pre-implantation development.

Telomeres are specialized structures required for the proper protection and replication of the end of linear chromosomes, such as those in eukaryotes. In mammals, telomeres are composed of long tracks of double stranded TTAGGG repeated DNA which can extend up to 10kb and 100kb in human and mice respectively. Telomeric DNA shortens after each round of cell division, leading ultimately to cell cycle arrest. However, stem cells can extend telomere length by the action of the telomerase, a specialized enzyme that adds new telomeric DNA. Telomere length must be properly controlled to ensure normal development, aging and to ensure cellular homeostasis. Interestingly, telomerase is not the only way to maintain telomere length. In about 10-15% of cancer, an alternative mechanism of telomere lengthening takes place. The ALT (Alternative Lengthening of Telomeres) pathway is a recombination based mode of telomere maintenance, which has been so far studied predominantly in cancer cells. How ALT is regulated and initiated is still not known. Previous studies identified a telomerase independent telomere lengthening in early mouse embryos, underlying that an ALT or ALT-like system can be used in a physiological context. The purpose of this research is to use mouse pre-implantation embryos and other embryonic cellular models to characterize the ALT (or ALT-like) pathway naturally occurring during early embryonic development. The research is organized into three aims: (WP1) developing tools to visualize and track telomere in mouse embryos, (WP2) characterize telomere regulation in mouse genetic models conditionally inactivated for Atrx and Daxx, (WP3) perform biochemical purification of proteins associated to telomeres of Atrx and Daxx conditional KO mouse embryonic stem cells lines. The identified proteins will be tested for their physiological relevance in mouse embryos.

Data: CORDIS, © European Union

Project objective

In the last decades, the progress in medicine have contributed to extend human lifespan considerably. Unfortunately, this aging of populations gives rise to the increased appearance of degenerative diseases and cancers, and therefore represents a critical problem for public health. During embryonic development, cellular proliferation is an essential process that is required to generate all the tissues and organs that contribute to the adult organism. However, alterations in the molecular mechanisms regulating this fundamental process can drive developmental defects and tumors. Cellular fail-safe systems evolved to prevent these events to happen. One of them is the natural shortening of chromosome ends, termed the telomeres. This “molecular clock” prevents cells from proliferating if their telomeres become critically short, which could lead to chromosomal alterations. This mechanism is responsible for cellular aging in Human. Unfortunately, cancer cells can bypass this process through the activation of telomere maintenance mechanism allowing for virtually unlimited proliferation. Interestingly, such maintenance mechanisms naturally occur during early embryonic development. The proposed research is aimed at understanding how telomeres are regulated in this system and under a physiological context. My expertise in mouse embryonic work associated with the competences in telomere biology of the host laboratory of Dr. Jerome Déjardin will likely be a suitable combination to answer these questions. On the long term, these researches could lead to the discovery of key factors regulating telomere maintenance. Finally, as the suppression of telomere length maintenance inhibits cell growth, the present proposal could contribute to the development of new treatments against cancer or precocious aging.

Original text from CORDIS.

Participants

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS · ParisCoordinatorFrance

TeloChromatin · Dissecting the chromatin dynamics at telomeres during mouse pre-implantation development.

Results in brief

Dissecting the chromatin dynamics at telomeres during mouse pre-implantation development.

Project objective

Participants

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