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.

X 失活 (XCI) 由 XIST 的上调触发，XIST以顺式包裹染色体，促进异染色质结构域 (Xi) 的形成。XIST在 XCI 启动之外的作用才刚刚开始被阐明。在这里，我们证明XIST缺失会损害人乳腺干细胞 (MaSC) 的分化并促进高致瘤性和转移性癌的出现。在 Xi 上，XIST缺陷会触发表观遗传变化和与 Polycomb 域重叠的基因的重新激活，包括介体亚基MED14。医疗14过量会导致介体水平升高和 MaSC 增强子景观和转录程序的过度激活，从而使分化变得不那么有利。我们进一步证明XIST和 Xi 转录不稳定性的丧失在预后不良的人类乳腺肿瘤中很常见。我们得出结论，XIST是人类乳腺上皮稳态的看门人，从而揭示了控制体细胞身份的范式，对我们理解性别特异性恶性肿瘤具有潜在影响。