Article

Xist RNA Is a Potent Suppressor of Hematologic Cancer in Mice

Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA
Cell (Impact Factor: 32.24). 02/2013; 152(4):727-42. DOI: 10.1016/j.cell.2013.01.034
Source: PubMed

ABSTRACT

X chromosome aneuploidies have long been associated with human cancers, but causality has not been established. In mammals, X chromosome inactivation (XCI) is triggered by Xist RNA to equalize gene expression between the sexes. Here we delete Xist in the blood compartment of mice and demonstrate that mutant females develop a highly aggressive myeloproliferative neoplasm and myelodysplastic syndrome (mixed MPN/MDS) with 100% penetrance. Significant disease components include primary myelofibrosis, leukemia, histiocytic sarcoma, and vasculitis. Xist-deficient hematopoietic stem cells (HSCs) show aberrant maturation and age-dependent loss. Reconstitution experiments indicate that MPN/MDS and myelofibrosis are of hematopoietic rather than stromal origin. We propose that Xist loss results in X reactivation and consequent genome-wide changes that lead to cancer, thereby causally linking the X chromosome to cancer in mice. Thus, Xist RNA not only is required to maintain XCI but also suppresses cancer in vivo.

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    • "Even though several lncRNAs have been discovered using model systems such as yeast, few have been proven to be involved in cancer-specific phenotypes and few are discovered to be involved in cancer metastasis (Gupta et al., 2010; Yuan et al., 2014). Currently, the majority of cancer studies of lncRNAs have focused on a few candidates (Cheetham et al., 2013), such as ANRIL (Yap et al., 2010), lncRNA-ATB (Yuan et al., 2014), PCAT1 (Prensner et al., 2011) in prostate cancer, XIST (Yildirim et al., 2013) in hematologic cancer, MALAT1 in lung cancer (Gutschner et al., 2013), and HOTAIR (Gupta et al., 2010) in breast cancer. These studies have enabled us to understand lncRNA biology in cancers; however, applying this knowledge toward therapeutics is the current need. "
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    • "In addition, multiple functions have been proposed for YY1 in X inactivation, including Xist RNA localization (Jeon and Lee, 2011) and Xist transcription (Makhlouf et al., 2014). Whereas Xist is not essential for maintenance of gene repression in somatic cells (Brown and Willard, 1994), loss of Xist in mice has recently been shown to lead to Xi reactivation in blood cells and leukemia (Yildirim et al., 2013). A genetic screen for epigenetic modifiers in mice has identified the SmcHD1 gene, which is required for maintaining DNA methylation and repression of Xi-linked gene promoters (Blewitt et al., 2008). "
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    ABSTRACT: In mammals, the noncoding Xist RNA triggers transcriptional silencing of one of the two X chromosomes in female cells. Here, we report a genetic screen for silencing factors in X chromosome inactivation using haploid mouse embryonic stem cells (ESCs) that carry an engineered selectable reporter system. This system was able to identify several candidate factors that are genetically required for chromosomal repression by Xist. Among the list of candidates, we identify the RNA-binding protein Spen, the homolog of split ends. Independent validation through gene deletion in ESCs confirms that Spen is required for gene repression by Xist. However, Spen is not required for Xist RNA localization and the recruitment of chromatin modifications, including Polycomb protein Ezh2. The identification of Spen opens avenues for further investigation into the gene-silencing pathway of Xist and shows the usefulness of haploid ESCs for genetic screening of epigenetic pathways. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Jul 2015 · Cell Reports
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    • "which is important for X chromosome inactivation (Hern andez-Mu~ noz et al. 2005). As loss of X chromosome inactivation causes an MDSlike disease in mice (Yildirim et al. 2013), differential splicing of macro-H2A.1 could potentially be relevant to disease processes. Isoform switches, wherein a previously minor isoform becomes the major isoform, were relatively rare but did occur. "
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