法国艾克斯-马赛大学Christophe Ginestier、索邦大学Raphaël Margueron等研究人员合作发现，XIST的缺失损害乳腺干细胞的分化，并通过中介体的过度激活增加肿瘤的发生。2022年5月20日，国际知名学术期刊《细胞》在线发表了这一成果。
研究人员表示，X失活（XCI）是由XIST的上调引发的，它顺式包裹染色体，促进异染色体域（Xi）的形成。XIST在启动XCI之外的作用才开始被阐明。
研究人员证明了XIST的缺失会损害人类乳腺干细胞（MaSC）的分化，并促进高度致瘤性和转移性癌的出现。在Xi上，XIST的缺失引发了表观遗传学的变化和重叠Polycomb结构域基因的重激活，包括中介体亚单位MED14。MED14的过量使用导致中介体水平的增加和MaSC增强子景观和转录程序的过度激活，使分化变得不那么有利。
研究人员进一步证明，在预后不佳的人类乳腺肿瘤中，XIST和Xi转录不稳定的损失是很常见的。因此，XIST是人类乳腺上皮细胞平衡的看门者，从而揭开了体细胞特性控制的一个范式，对人们理解性别特异性恶性肿瘤具有潜在的影响。
附：英文原文
Title: XIST loss impairs mammary stem cell differentiation and increases tumorigenicity through Mediator hyperactivation
Author: Laia Richart, Mary-Loup Picod-Chedotel, Michel Wassef, Manon Macario, Setareh Aflaki, Marion A. Salvador, Tiphaine Héry, Aurélien Dauphin, Julien Wicinski, Véronique Chevrier, Sonia Pastor, Geoffrey Guittard, Samuel Le Cam, Hanya Kamhawi, Rémy Castellano, Géraldine Guasch, Emmanuelle Charafe-Jauffret, Edith Heard, Raphal Margueron, Christophe Ginestier
Issue&Volume: 2022-05-20
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 demonstratethat XIST loss impairs differentiation of human mammary stem cells (MaSCs) and promotes emergenceof highly tumorigenic and metastatic carcinomas. On the Xi, XIST deficiency triggers epigenetic changes and reactivation of genes overlapping Polycombdomains, including Mediator subunit MED14. MED14 overdosage results in increased Mediator levels and hyperactivation of the MaSC enhancerlandscape and transcriptional program, making differentiation less favorable. We furtherdemonstrate 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 paradigmin the control of somatic cell identity with potential consequences for our understandingof gender-specific malignancies.
DOI: 10.1016/j.cell.2022.04.034
Source: https://www.cell.com/cell/fulltext/S0092-8674(22)00532-3