Deciphering the impact of X-chromosome inactivation in the germline – X-REACT

In mammals, the most drastic transition in cell fate coincides with the emergence of the germline in the embryo. Occurring in both sexes, epigenetic reprogramming is essential for the formation of reproductive cells in vivo, and for the perpetuation of the species. Reactivation of the inactive X chromosome, an epigenetic hallmark of female cells, accompanies the acquisition of germline identity in female. This leads to a transient excess of X-linked gene products in the germline of XX females compared to XY males, at the onset of gonadal sex determination. The biological impact and significance of this specific epigenetic characteristics is unknown. However, the presence of a non-reactivated X chromosome could be detrimental to homologous chromosome pairing and meiosis, and would thus result in maternally inherited sex-chromosome aneuploidies such as XO and XXY syndromes in humans. It is such critical to understand X-chromosome reactivation and its impact.
Here, we aim to investigate the specificity and principles of female germline epigenetic reprogramming. There is an important gap in our knowledge concerning how X-chromosome reactivation occurs during female germline formation, and whether this impacts epigenetic regulation genome-wide. Our objectives are i) to model the X-chromosome reactivation and sex-specific reprogramming, ii) to perturb X-chromosome reactivation and study the consequences of its failure, and iii) to investigate the reciprocal influence of X-chromosome activity and global genome transcription. Using a combination of in vivo mouse models and culture-based systems of germ cells, we plan to employ low-input epigenomics and transcriptomics profiling, genetics and theoretical modelling to map and functionally infer the sex-specific regulation of early germline development. Ultimately, this work will have broader implications for sex-chromosome related infertility, stem cell and reproductive medicine as well as epigenetic inheritance.