XIST loss impairs mammary stem cell differentiation and increases tumorigenicity through Mediator hyperactivation
Menée in vitro et à l'aide d'une xénogreffe sur un modèle murin, cette étude met en évidence un mécanisme par lequel la perte de l'expression du gène XIST altère la différenciation des cellules souches mammaires et favorise l'émergence de carcinomes hautement tumorigènes et métastatiques via l'hyperactivation du Médiateur
X inactivation (XCI) is triggered by upregulation of XIST, which coats the chromosome in cis, promoting formation of a heterochromatic domain (Xi). XIST role beyond initiation of XCI is only beginning to be elucidated. Here, we demonstrate that XIST loss impairs differentiation of human mammary stem cells (MaSCs) and promotes emergence of highly tumorigenic and metastatic carcinomas. On the Xi, XIST deficiency triggers epigenetic changes and reactivation of genes overlapping Polycomb domains, including Mediator subunit MED14. MED14 overdosage results in increased Mediator levels and hyperactivation of the MaSC enhancer landscape and transcriptional program, making differentiation less favorable. We further demonstrate that loss of XIST and Xi transcriptional instability is common among human breast tumors of poor prognosis. We conclude that XIST is a gatekeeper of human mammary epithelium homeostasis, thus unveiling a paradigm in the control of somatic cell identity with potential consequences for our understanding of gender-specific malignancies.
Cell 2022