1. XIST loss impairs mammary stem cell differentiation and increases tumorigenicity through Mediator hyperactivation.
- Author
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Richart, Laia, Picod-Chedotel, Mary-Loup, Wassef, Michel, Macario, Manon, Aflaki, Setareh, Salvador, Marion A., Héry, Tiphaine, Dauphin, Aurélien, Wicinski, Julien, Chevrier, Véronique, Pastor, Sonia, Guittard, Geoffrey, Le Cam, Samuel, Kamhawi, Hanya, Castellano, Rémy, Guasch, Géraldine, Charafe-Jauffret, Emmanuelle, Heard, Edith, Margueron, Raphaël, and Ginestier, Christophe
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X chromosome , *STEM cells , *HUMAN stem cells , *CELL differentiation , *BREAST cancer prognosis , *SOMATIC cells - Abstract
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. [Display omitted] • XIST -null cells display reactivation of a few X-linked genes, including MED14 • MED14 overdosage impacts stem cell homeostasis through Mediator stabilization • Loss of XIST enhances the tumorigenic potential of cells upon transformation • Xi transcriptional reactivation is common among aggressive breast tumors Outside the context of initiating X chromosome inactivation, XIST contributes to human mammary stem cell homeostasis, and loss of XIST and Xi transcriptional instabilities enhances tumorigenesis and is a common feature among human breast tumors with poor prognosis. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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