Xist RNA is a potent suppressor of hematologic cancer in mice.
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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Article: Noncoding RNAs and cancer[Show abstract] [Hide abstract]
ABSTRACT: New and diverse groups of noncoding RNAs are beginning to be discovered. These noncoding RNAs are grouped based on their sizes, genomic positions, or distinctive functions ranging from the regulation of chromatin structure and gene expression to genome stability maintenance. Among noncoding RNAs, microRNAs are the best studied and understood small RNAs with direct and indirect roles in normal and in cancer cells. Given the high rate of transcription from noncoding parts of the genome, other noncoding elements are also of great interest. It is also of interest to understand that there may be interesting cases of crosstalk and/or coregulation between the noncoding and the coding portion of the genome. Therefore, deregulated expression of noncoding RNAs can be considered to cause significant alterations in cancer cells. The complexities of the genome and transcriptome still remain mesmerizing. As we better understand these complexities, we will be able to improve our understanding of human conditions and will hopefully develop tools to improve the ways in which we deal with diseases, particularly cancer. Here, based on recent findings, we provide a descriptive profile of noncoding RNA classes, their roles, and their potential contributions to the complex events of tumorigenesisTurkish Journal of Biology 01/2014; 38(6):817. DOI:10.3906/biy-1404-104 · 1.22 Impact Factor
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ABSTRACT: Hematopoietic stem cells (HSCs) possess unique gene expression programs that enforce their identity and regulate lineage commitment. Long non-coding RNAs (lncRNAs) have emerged as important regulators of gene expression and cell fate decisions, although their functions in HSCs are unclear. Here we profiled the transcriptome of purified HSCs by deep sequencing and identified 323 unannotated lncRNAs. Comparing their expression in differentiated lineages revealed 159 lncRNAs enriched in HSCs, some of which are likely HSC specific (LncHSCs). These lncRNA genes share epigenetic features with protein-coding genes, including regulated expression via DNA methylation, and knocking down two LncHSCs revealed distinct effects on HSC self-renewal and lineage commitment. We mapped the genomic binding sites of one of these candidates and found enrichment for key hematopoietic transcription factor binding sites, especially E2A. Together, these results demonstrate that lncRNAs play important roles in regulating HSCs, providing an additional layer to the genetic circuitry controlling HSC function. Copyright © 2015 Elsevier Inc. All rights reserved.
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ABSTRACT: Cellular reprogramming highlights the epigenetic plasticity of the somatic cell state. Long noncoding RNAs (lncRNAs) have emerging roles in epigenetic regulation, but their potential functions in reprogramming cell fate have been largely unexplored. We used single-cell RNA sequencing to characterize the expression patterns of over 16,000 genes, including 437 lncRNAs, during defined stages of reprogramming to pluripotency. Self-organizing maps (SOMs) were used as an intuitive way to structure and interrogate transcriptome data at the single-cell level. Early molecular events during reprogramming involved the activation of Ras signaling pathways, along with hundreds of lncRNAs. Loss-of-function studies showed that activated lncRNAs can repress lineage-specific genes, while lncRNAs activated in multiple reprogramming cell types can regulate metabolic gene expression. Our findings demonstrate that reprogramming cells activate defined sets of functionally relevant lncRNAs and provide a resource to further investigate how dynamic changes in the transcriptome reprogram cell state. Copyright © 2015 Elsevier Inc. All rights reserved.