X-chromosome inactivation (XCI) during early female development is an essential epigenetic process that is required to achieve appropriate dosage between the sexes for X-linked gene products. We are interested in understanding how the differential treatment of the two X chromosomes in the same nucleus is set up during development and how this differential expression is then maintained, or reversed in certain circumstances, either normally or in a disease context such as cancer. The establishment of XCI involves the non-coding Xist RNA that triggers chromosome-wide chromatin re-organisation and gene silencing. Our lab is studying the role of these epigenetic changes as well as the mechanisms of differential gene silencing along the X chromosome.

In particular we have studied the role of the Xist-recruited SPEN protein, that triggers gene silencing and dampens expression of genes that escape XCI (Dossin et al, 2020). We have also recently investigated the role of PRC1 and PRC2 Polycomb complexes in vivo and uncovered essential and independent roles for each complex in maintaining the silent state of the inactive X in extraembryonic tissues.

Finally, our studies using chromosome conformation capture techniques have revealed that the loss of topologically associating domains (TADs) is an early event during XCI and genes that escape XCIform TAD-like structures (Giorgetti et al, 2016; Collombet et al, 2020). We are exploring whether these domains are a cause or a consequence of gene reactivation on the Xi. Our recent insights into the relationship between chromatin states, 3D chromosome organisation and escape from XCI will be presented, considering the implications of increased X-linked gene dosage due to escape for normal female physiology, as well as in cancer.