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Female-specific epigenetic mechanisms may contribute to tumour progression

05/27/2022

The teams of Raphaël Margueron (Institut Curie, Inserm, CNRS) and Christophe Ginestier (Institut Paoli Calmettes and Aix-Marseille University) describe the epigenetic role of a non-coding RNA in the development of aggressive tumours, particularly in breast cancer. These results could explain gender bias in the predisposition to certain pathologies, and have recently been published in the journal Cell.

Proposed cover for the issue of Cell.
Artwork done by Bertsy Goic, PhD: Draw in Science - illustrate to communicate

Mammals have two sex chromosomes. Female mammals have two X chromosomes, while males have one X and one Y chromosome. The role of a specific non-coding RNA, called XIST, in initiating the inactivation of one of the two female X chromosomes was already known. The purpose of this inactivation is to block the dual expression of genes located on this chromosome, as this affects cell viability. In this new study, the research teams demonstrate that XIST not only plays a role in triggering the inactivation of the X chromosome but also in maintaining it throughout the life of the cells. Loss of XIST had a significant effect on the homeostasis of breast tissue and impacted tumour development in the studied cell lines. Moreover, the researchers observed that there is a tendency for XIST to be absent from the most aggressive breast tumours, along with a reactivation of several genes from inactive X.

Among these reactivated genes, the researchers identified the gene coding for MED14, an essential subunit within the Mediator protein complex involved in the control of gene expression. Increased dosage of MED14 expression will impact on the activity of Mediator and contribute to the disruption of mammary stem cell differentiation, therefore impacting the development of aggressive tumour cells.

As this epigenetic mechanism is specific to the presence of two X chromosomes, these results will play a major role in the study of predispositions to pathologies linked to the gender of the individual.

REFERENCE

Loss of XIST impairs human mammary stem cell differentiation and increases tumorigenicity through enhancer and Mediator complex hyperactivation. Laia Richart^1,$, Mary-Loup Picod-Chedotel^2,$, Michel Wassef¹, Manon Macario², Setareh Aflaki¹, Marion A. Salvador², Tiphaine Héry¹, Aurélien Dauphin¹, Julien Wicinski², Véronique Chevrier², Sonia Pastor³, Geoffrey Guittard³, Samuel Le Cam¹, Hanya Kamhawi², Rémy Castellano⁴, Géraldine Guasch², Emmanuelle Charafe-Jauffret^2,5, Edith Heard^6,7, Raphaël Margueron^1,*, Christophe Ginestier^2,*. Cell. 20 mai 2022.

ARTWORK

Proposed cover for this issue of Cell done by Bertsy Goic, PhD, Draw in science - illustrate to communicate