Our goal

Females are mosaics

Why study X-chromosome inactivation?

During development, specialized cell types emerge from a common single progenitor thanks to the expression of specific sets of genes, and the silencing of other genes. The differences between cell types are not due to DNA sequence differences but rather to what is often referred to as epigenetic variation.

The aim of the group of Edith Heard is to understand how cells can express their genomes differentially and in a stable, although sometimes reversible, manner during development, using X-chromosome inactivation as our model. X inactivation is a normal process, entailing the silencing of one of the two X chromosomes in female mammals. Once established the silent state is stably maintained through cell divisions and throughout the adult life, but can be reversed at certain stages of development, in the germ line and possibly in cancer cells. The inactive X provides a unique model of chromosome-wide epigenetic silencing.

Our questions

Studying the process of X chromosome inactivation allows to unveil molecular mechanisms involved in establishing, maintaining and reversing heterochromatin. We are interested in four principal questions :

• What underlies the control of the initiation of X-chromosome inactivation?
• How is transcriptional repression established?
• How is the inactive state faithfully inherited through cellular division?  
• How does tumor development affect maintenance of the inactive state of the X chromosome ?

Our tools

To analyse the early steps of X-chromosome inactivation we study mouse embryos and mouse embryonic stem cells. In parallel, we also use human cancer cell lines, as well as breast tumor samples in collaboration with doctors at the Curie Hospital, to investigate the mechanisms underlying epigenetic instability in the context of tumor development.

We couple classic molecular approaches with the analysis of cellular behavior at the single-cell level, in fixed or live samples, thanks to the the Institut Curie’s imaging platform and the state-of-the-art microscopy tools and expertise available within the Genetics and Developmental Biology department. These approaches are combined with large-scale genomic and epigenomic techniques made possible thanks to the various technological departments of the Institut Curie. Our work is especially focused on changes in chromatin structure and nuclear organization associated with heterochromatin formation, as well as the role of non-coding RNAs such as the remarkable Xist RNA which is expressed specifically from the inactive X and underlies the initiation of X inactivation.

Xist RNA coating of the inactive X chromosome