Project description
Understanding the connection between chromatin and DNA repair
Depending on its needs, a cell can alter the structure of its chromatin from a condensed, inactive form to a less condensed, active state, and vice versa. This reversible nature of chromatin shapes gene regulation and cellular differentiation. Funded by the Marie Skłodowska-Curie Actions programme, the XICUT project aims to investigate the DNA damage response within chromatin and how that affects DNA repair. Researchers will focus on the inactive X chromosome in female mammals, exploring how its chromatin state reacts to DNA double-strand breaks. The work will provide important insights into repair mechanisms and chromatin dynamics.
Objective
The DNA damage response takes place on a chromatin substrate and triggers profound chromatin alterations. Chromatin states vary substantially between genomic regions, driving distinct gene expression profiles and also different DNA damage repair responses. One striking example is the heterochromatinization of an entire chromosome, the inactive X chromosome in female mammals, that is silenced during embryonic development by facultative heterochromatin formation. How the facultative heterochromatin state of the inactive X responds to DNA damage and impacts DNA repair is poorly understood. My research project aims at identifying chromatin changes that accompany the repair of the most cytotoxic form of DNA damage, DNA double-strand breaks (DSBs), in facultative heterochromatin and the mechanisms that ensure the establishment and maintenance of the inactive X chromosome in response to DNA damage in mammalian cells. To generate DSBs, I use the CRISPR/Cas9 technology that allows sequence-specific targeting of the Cas9 nuclease. Thanks to available bioinformatic tools, I can discriminate between active and inactive X chromosomes, analyze the genomic instability profiles induced around the break sites and decipher the repair pathway involved. In parallel, I will profile the chromatin marks associated with the inactive X chromosome in the vicinity of DSBs to assess the impact of DNA damage and repair on heterochromatin maintenance. Moreover, I will test the hypothesis that the high level of replicative stress-induced breaks in embryonic stem cells could drive heterochromatin establishment and thus skew the choice of the inactive X chromosome. For this, I will study the impact of generating DSBs on one X chromosome of mouse stem cells on their differentiation potential and their propension to inactivate the damaged X chromosome. Together, this work should shed light on the interplay between the DSB response and facultative heterochromatin states.
Fields of science
Keywords
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Funding Scheme
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinator
75794 Paris
France