Agnese LODA

Sex chromosomes are the first source of sex differences in development. From the earliest stages of life, XX and XY embryos express genes at different levels, but the consequences of this sex-specific gene expression for pregnancy outcomes and lifelong health remain largely unexplored.

In female embryos, one of the two X chromosomes is largely silenced by X-chromosome inactivation (XCI), the epigenetic process that balances X-linked gene dosage between the sexes and allows female embryos to survive throughout development. Although most X-linked genes are silenced during XCI, a subset escapes this silencing, resulting in higher expression levels in females than in males.

How escape from XCI is regulated is poorly understood. Yet variation in the dosage of X-linked “escapees” is expected to contribute to sexual dimorphism in different contexts, including sex-specific responses to environmental challenges during development and differences in disease susceptibility. However, the mechanisms by which X-linked genes establish sex-specific regulatory programs and the impact of these programs on embryogenesis and adult health remain unknown.
Our lab addresses these fundamental questions by integrating molecular and developmental biology with functional genetics to first dissect the mechanisms that allow escapees to bypass XCI and then define their exact function across developmental contexts at the molecular, cellular, and tissue levels.

We use genetically engineered in vitro and in vivo models to manipulate X-linked gene expression and protein dosage, together with CRISPR-based genetic screens and targeted mutagenesis of putative regulators, to ultimately unveil the impact of X-linked gene dosage on fetal growth and survival.

Our work will uncover fundamental mechanisms of developmental gene regulation across time and space and reveal the extent to which X-linked gene activity contributes to differences between XX and XY individuals, with important implications for human health and reproductive medicine.

The Epigenetics and Sex Differences Lab at Institut Imagine is also affiliated with the Developmental and Stem Cell Biology Department at the Institut Pasteur.