XIST

Gene Summary

Gene:XIST; X inactive specific transcript (non-protein coding)
Aliases: SXI1, swd66, DXS1089, DXS399E, LINC00001, NCRNA00001
Location:Xq13.2
Summary:X inactivation is an early developmental process in mammalian females that transcriptionally silences one of the pair of X chromosomes, thus providing dosage equivalence between males and females. The process is regulated by several factors, including a region of chromosome X called the X inactivation center (XIC). The XIC comprises several non-coding and protein-coding genes, and this gene was the first non-coding gene identified within the XIC. This gene is expressed exclusively from the XIC of the inactive X chromosome, and is essential for the initiation and spread of X-inactivation. The transcript is a spliced RNA. Alternatively spliced transcript variants have been identified, but their full length sequences have not been determined. Mutations in the XIST promoter cause familial skewed X inactivation. [provided by RefSeq, Apr 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 13 March, 2017

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 13 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 13 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: XIST (cancer-related)

Song P, Ye LF, Zhang C, et al.
Long non-coding RNA XIST exerts oncogenic functions in human nasopharyngeal carcinoma by targeting miR-34a-5p.
Gene. 2016; 592(1):8-14 [PubMed] Related Publications
Long non-coding RNA (lncRNA) X inactivate-specific transcript (XIST) has been verified as an oncogenic gene in several human malignant tumors, and its dysregulation was closed associated with tumor initiation, development and progression. Nevertheless, whether the aberrant expression of XIST in human nasopharyngeal carcinoma (NPC) is corrected with malignancy, metastasis or prognosis has not been elaborated. Here, we discovered that XIST was up-regulated in NPC tissues and higher expression of XIST contributed to a markedly poorer survival time. In addition, multivariate analysis demonstrated XIST was an independent risk factor for prognosis. XIST over-expression enhanced, while XIST silencing hampered the cell growth in NPC. Additionally, mechanistic analysis revealed that XIST up-regulated the expression of miR-34a-5p targeted gene E2F3 through acting as a competitive 'sponge' of miR-34a-5p. Taking all into account, we concluded that XIST functioned as an oncogene in NPC through up-regulating E2F3 in part through 'spongeing' miR-34a-5p.

Soudyab M, Iranpour M, Ghafouri-Fard S
The Role of Long Non-Coding RNAs in Breast Cancer.
Arch Iran Med. 2016; 19(7):508-17 [PubMed] Related Publications
Long non-coding RNA (lncRNA) genes are an important population of non-coding RNAs with defined key roles in normal development as well as tumorigenesis process. Evidences suggest that they can be classified as tumor suppressor genes or oncogenes according to their functions and expression pattern in tumoral tissues. They have been shown to regulate the plasticity of cancer stem cells. Their important roles in the regulation of cancer-related pathways in addition to deregulation of their expression in a number of cancers have suggested that they can be used as markers for cancer detection and prognosis, as well as targets for cancer treatment. Deregulation of a number of lncRNAs, such as HOTAIR, XIST, MALAT, and H19 has been detected in breast cancer samples and cell lines. In addition, the association between lncRNAs signature and breast cancer patients' survival has been assessed in various studies. Here, the expression patterns of lncRNAs in breast cancer, as well as their significance in prognosis and patient treatment are discussed.

Schouten PC, Vollebergh MA, Opdam M, et al.
High XIST and Low 53BP1 Expression Predict Poor Outcome after High-Dose Alkylating Chemotherapy in Patients with a BRCA1-like Breast Cancer.
Mol Cancer Ther. 2016; 15(1):190-8 [PubMed] Related Publications
In previous studies, high expression of XIST and low expression of 53BP1 were respectively associated with poor systemic therapy outcome in patients and therapy resistance in BRCA1-deficient mouse tumor models, but have not been evaluated in BRCA1-deficient patients. Previously, we demonstrated that classifying breast cancer copy number profiles as BRCA1-like or non-BRCA1-like identified patients enriched for defects in BRCA1 that benefit from high-dose (HD) alkylating chemotherapy compared with a conventional standard regimen. We investigated whether XIST and 53BP1 expression predicted poor outcome of HD chemotherapy within 28 BRCA1-like patients from a trial randomizing between HD [4 cycles 5-fluorouracil, epirubicin, cyclophosphamide (FEC) followed by 1 cycle HD carboplatin, thiotepa, cyclophosphamide] or conventional chemotherapy (5 cycles FEC), for which both XIST and 53BP1 statuses were available. High RNA expression of XIST (n = 5) and low protein expression of 53BP1 (n = 3) expression did not coincide. Patients with either one had poor outcome after treatment with HD chemotherapy, whereas patients with low expression of XIST and high expression of 53BP1 derived substantial benefit of this regimen on recurrence-free survival, disease-free survival, and overall survival, corroborating preclinical findings. XIST and 53BP1 may be predictive biomarkers in BRCA1-like breast cancer.

Weil PP, Hensel KO, Weber D, Postberg J
An expanding universe of noncoding RNAs between the poles of basic science and clinical investigations.
Epigenomics. 2016; 8(3):317-9 [PubMed] Related Publications
The Keystone Symposium 'MicroRNAs and Noncoding RNAs in Cancer', Keystone, CO, USA, 7-12 June 2015 Since the discovery of RNAi, great efforts have been undertaken to unleash the potential biomedical applicability of small noncoding RNAs, mainly miRNAs, involving their use as biomarkers for personalized diagnostics or their usability as active agents or therapy targets. The research's focus on the noncoding RNA world is now slowly moving from a phase of basic discoveries into a new phase, where every single molecule out of many hundreds of cataloged noncoding RNAs becomes dissected in order to investigate these molecules' biomedical relevance. In addition, RNA classes neglected before, such as long noncoding RNAs or circular RNAs attract more attention. Numerous timely results and hypotheses were presented at the 2015 Keystone Symposium 'MicroRNAs and Noncoding RNAs in Cancer'.

Kang J, Lee HJ, Jun SY, et al.
Cancer-Testis Antigen Expression in Serous Endometrial Cancer with Loss of X Chromosome Inactivation.
PLoS One. 2015; 10(9):e0137476 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cancer-testis antigens (CTAs) are potential targets for cancer immunotherapy. Many CTAs are located on the X chromosome and are epigenetically regulated. Loss of X chromosome inactivation (XCI) is observed in breast and ovarian cancers and is thought to be related to the overexpression of CTAs. We investigated the relation between expression of CTAs and loss of XCI in endometrial cancer.
MATERIALS AND METHODS: We used data generated by The Cancer Genome Atlas Genome Data Analysis Centers and data for Xist knockout mice available at the Gene Expression Omnibus.
RESULTS: The status of XCI was estimated by methylation status, and deletion or gain of the X chromosome. The endometrial cancers were classified into the following three groups: preserved inactivated X chromosome (Xi) (n = 281), partial reactivation of Xi (n = 52), and two copies of active X group (n = 38). Loss of XCI was more common in serous adenocarcinoma. Expression of CTAs increased in endometrial cancer with loss of XCI, which was accompanied by global hypomethylation. Expression of CTAs did not increase in Xist knockout mice.
CONCLUSIONS: Loss of XCI is common in serous adenocarcinoma. Global hypomethylation, and not loss of XCI, is the main mechanism of overexpression of CTAs.

Sun M, Nie FQ, Wang ZX, De W
Involvement of lncRNA dysregulation in gastric cancer.
Histol Histopathol. 2016; 31(1):33-9 [PubMed] Related Publications
Benefiting from the fast development of sequencing technique and bioinformatics methods, more and more new long non-coding RNAs (lncRNAs) are discovered and identified. lncRNAs were firstly thought to be transcription noise that from genome desert without biological function; however, as the discovery of lncRNA XIST and HOTAIR uncovers the emerging roles of lncRNAs in development and tumorigenesis. In the past decades, accumulating evidence have indicated that lncRNAs involve in a wide range of biological functions, such as X-chromosome inactivation, reprogramming stem cell pluripotency, regulation of the immune response and carcinogenesis. Although lots of studies have demonstrated that dysregulation of lncRNAs involve in diverse diseases including cancers, the underlying molecular mechanisms of lncRNAs are not well documented. Interestingly, our previous studies and others' have shown that numerous of lncRNAs expression was misregulated in gastric cancer. In this review, we will focus on the dysregulated lncRNAs and their biological function and underlying pathways or mechanisms in GC. Finally, we will discuss the potential roles of lncRNAs acting as biomarkers or therapeutic targets in GC patients.

Sun Z, Prodduturi N, Sun SY, et al.
Chromosome X genomic and epigenomic aberrations and clinical implications in breast cancer by base resolution profiling.
Epigenomics. 2015; 7(7):1099-110 [PubMed] Related Publications
AIM: Abnormal inactivation or loss of inactivated X chromosome (Xi) is implicated in women's cancer. However, the underlying mechanisms and clinical relevance are little known.
MATERIALS & METHODS: High-throughput sequencing was conducted on breast cancer cell lines for copy number, RNA expression and 5'-methylcytosine in ChrX. The results were examined in primary breast tumors.
RESULTS & CONCLUSION: Breast cancer cells demonstrated reduced or total loss of hemimethylation. Most cell lines lost part or one of X chromosomes. Cell lines without ChrX loss were more active in gene expression. DNA methylation was corroborated with Xi control lincRNA XIST. Similar transcriptome and DNA methylation changes were observed in primary breast cancer datasets with clinical phenotype associations. Dramatic genomic and epigenomic changes in ChrX may be used for potential diagnostic or prognostic markers in breast cancer.

Richard JL, Ogawa Y
Understanding the Complex Circuitry of lncRNAs at the X-inactivation Center and Its Implications in Disease Conditions.
Curr Top Microbiol Immunol. 2016; 394:1-27 [PubMed] Related Publications
Balanced gene expression is a high priority in order to maintain optimal functioning since alterations and variations could result in acute consequences. X chromosome inactivation (X-inactivation) is one such strategy utilized by mammalian species to silence the extra X chromosome in females to uphold a similar level of expression between the two sexes. A functionally versatile class of molecules called long noncoding RNA (lncRNA) has emerged as key regulators of gene expression and plays important roles during development. An lncRNA that is indispensable for X-inactivation is X-inactive specific transcript (Xist), which induces a repressive epigenetic landscape and creates the inactive X chromosome (Xi). With recent advents in the field of X-inactivation, novel positive and negative lncRNA regulators of Xist such as Jpx and Tsix, respectively, have broadened the regulatory network of X-inactivation. Xist expression failure or dysregulation has been implicated in producing developmental anomalies and disease states. Subsequently, reactivation of the Xi at a later stage of development has also been associated with certain tumors. With the recent influx of information about lncRNA biology and advancements in methods to probe lncRNA, we can now attempt to understand this complex network of Xist regulation in development and disease. It has become clear that the presence of an extra set of genes could be fatal for the organism. Only by understanding the precise ways in which lncRNAs function can treatments be developed to bring aberrations under control. This chapter summarizes our current understanding and knowledge with regard to how lncRNAs are orchestrated at the X-inactivation center (Xic), with a special focus on how genetic diseases come about as a consequence of lncRNA dysregulation.

Ren C, Li X, Wang T, et al.
Functions and Mechanisms of Long Noncoding RNAs in Ovarian Cancer.
Int J Gynecol Cancer. 2015; 25(4):566-9 [PubMed] Related Publications
Long noncoding RNAs (lncRNAs) are longer than 200-nucleotide, noncoding transcripts in length, have a variety of biological functions, and are closely associated with tumor development. Ovarian cancer, as 1 of the 3 common gynecological malignancies, is the leading cause of death in women with gynecological malignant tumor. In this study, a review of the literature found that lncRNAs H19, LSINCT5, and XIST have a close relationship to the development of ovarian cancer occurrence, growth, invasion, and metastasis, and they can promote ovarian cancer cell proliferation. Hence, in this article, the progress of above-mentioned 3 kinds of lncRNAs in ovarian cancer was reviewed and designed to help in the diagnosis, treatment, and prognosis of ovarian cancer.

Lin IH, Chen DT, Chang YF, et al.
Hierarchical clustering of breast cancer methylomes revealed differentially methylated and expressed breast cancer genes.
PLoS One. 2015; 10(2):e0118453 [PubMed] Free Access to Full Article Related Publications
Oncogenic transformation of normal cells often involves epigenetic alterations, including histone modification and DNA methylation. We conducted whole-genome bisulfite sequencing to determine the DNA methylomes of normal breast, fibroadenoma, invasive ductal carcinomas and MCF7. The emergence, disappearance, expansion and contraction of kilobase-sized hypomethylated regions (HMRs) and the hypomethylation of the megabase-sized partially methylated domains (PMDs) are the major forms of methylation changes observed in breast tumor samples. Hierarchical clustering of HMR revealed tumor-specific hypermethylated clusters and differential methylated enhancers specific to normal or breast cancer cell lines. Joint analysis of gene expression and DNA methylation data of normal breast and breast cancer cells identified differentially methylated and expressed genes associated with breast and/or ovarian cancers in cancer-specific HMR clusters. Furthermore, aberrant patterns of X-chromosome inactivation (XCI) was found in breast cancer cell lines as well as breast tumor samples in the TCGA BRCA (breast invasive carcinoma) dataset. They were characterized with differentially hypermethylated XIST promoter, reduced expression of XIST, and over-expression of hypomethylated X-linked genes. High expressions of these genes were significantly associated with lower survival rates in breast cancer patients. Comprehensive analysis of the normal and breast tumor methylomes suggests selective targeting of DNA methylation changes during breast cancer progression. The weak causal relationship between DNA methylation and gene expression observed in this study is evident of more complex role of DNA methylation in the regulation of gene expression in human epigenetics that deserves further investigation.

Chaligné R, Popova T, Mendoza-Parra MA, et al.
The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer.
Genome Res. 2015; 25(4):488-503 [PubMed] Free Access to Full Article Related Publications
Disappearance of the Barr body is considered a hallmark of cancer, although whether this corresponds to genetic loss or to epigenetic instability and transcriptional reactivation is unclear. Here we show that breast tumors and cell lines frequently display major epigenetic instability of the inactive X chromosome, with highly abnormal 3D nuclear organization and global perturbations of heterochromatin, including gain of euchromatic marks and aberrant distributions of repressive marks such as H3K27me3 and promoter DNA methylation. Genome-wide profiling of chromatin and transcription reveal modified epigenomic landscapes in cancer cells and a significant degree of aberrant gene activity from the inactive X chromosome, including several genes involved in cancer promotion. We demonstrate that many of these genes are aberrantly reactivated in primary breast tumors, and we further demonstrate that epigenetic instability of the inactive X can lead to perturbed dosage of X-linked factors. Taken together, our study provides the first integrated analysis of the inactive X chromosome in the context of breast cancer and establishes that epigenetic erosion of the inactive X can lead to the disappearance of the Barr body in breast cancer cells. This work offers new insights and opens up the possibility of exploiting the inactive X chromosome as an epigenetic biomarker at the molecular and cytological levels in cancer.

Yao Y, Ma J, Xue Y, et al.
Knockdown of long non-coding RNA XIST exerts tumor-suppressive functions in human glioblastoma stem cells by up-regulating miR-152.
Cancer Lett. 2015; 359(1):75-86 [PubMed] Related Publications
Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Great interest persists in useful therapeutic targets in GBM. Aberrant expression of long non-coding RNAs (lncRNAs) has been functionally associated with many cancers. Here, we elucidated the function and the possible molecular mechanisms of lncRNA XIST in human glioblastoma stem cells (GSCs). Our results proved that XIST expression was up-regulated in glioma tissues and GSCs. Functionally, knockdown of XIST exerted tumor-suppressive functions by reducing cell proliferation, migration and invasion as well as inducing apoptosis. The in vivo studies also showed that knockdown of XIST suppressed tumor growth and produced high survival in nude mice. Further, there was reciprocal repression between XIST and miR-152. Mechanistic investigations defined the direct binding ability of the predicted miR-152 binding site on the XIST. In addition, XIST and miR-152 are probably in the same RNA induced silencing complex (RISC). Finally, miR-152 mediated the tumor-suppressive effects that knockdown of XIST exerted. Taken together, these results provided a comprehensive analysis of XIST in GSCs and important clues for understanding the key roles of lncRNA-miRNA functional network in human glioma.

Giuliano M, Herrera S, Christiny P, et al.
Circulating and disseminated tumor cells from breast cancer patient-derived xenograft-bearing mice as a novel model to study metastasis.
Breast Cancer Res. 2015; 17:3 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Real-time monitoring of biologic changes in tumors may be possible by investigating the transitional cells such as circulating tumor cells (CTCs) and disseminated tumor cells in bone marrow (BM-DTCs). However, the small numbers of CTCs and the limited access to bone marrow aspirates in cancer patients pose major hurdles. The goal of this study was to determine whether breast cancer (BC) patient-derived xenograft (PDX) mice could provide a constant and renewable source of CTCs and BM-DTCs, thereby representing a unique system for the study of metastatic processes.
METHODS: CTCs and BM-DTCs, isolated from BC PDX-bearing mice, were identified by immunostaining for human pan-cytokeratin and nuclear counterstaining of red blood cell-lysed blood and bone marrow fractions, respectively. The rate of lung metastases (LM) was previously reported in these lines. Associations between the presence of CTCs, BM-DTCs, and LM were assessed by the Fisher's Exact and Cochran-Mantel-Haenszel tests. Two separate genetic signatures associated with the presence of CTC clusters and with lung metastatic potential were computed by using the expression arrays of primary tumors from different PDX lines and subsequently overlapped to identify common genes.
RESULTS: In total, 18 BC PDX lines were evaluated. CTCs and BM-DTCs, present as either single cells or clusters, were detected in 83% (15 of 18) and 62.5% (10 to16) of the lines, respectively. A positive association was noted between the presence of CTCs and BM-DTCs within the same mice. LM was previously found in 9 of 18 (50%) lines, of which all nine had detectable CTCs. The presence of LM was strongly associated with the detection of CTC clusters but not with individual cells or detection of BM-DTCs. Overlapping of the two genetic signatures of the primary PDX tumors associated with the presence of CTC clusters and with lung metastatic potential identified four genes (HLA-DP1A, GJA1, PEG3, and XIST). This four-gene profile predicted distant metastases-free survival in publicly available datasets of early BC patients.
CONCLUSION: This study suggests that CTCs and BM-DTCs detected in BC PDX-bearing mice may represent a valuable and unique preclinical model for investigating the role of these rare cells in tumor metastases.

Sun M, Kraus WL
From discovery to function: the expanding roles of long noncoding RNAs in physiology and disease.
Endocr Rev. 2015; 36(1):25-64 [PubMed] Free Access to Full Article Related Publications
Long noncoding RNAs (lncRNAs) are a relatively poorly understood class of RNAs with little or no coding capacity transcribed from a set of incompletely annotated genes. They have received considerable attention in the past few years and are emerging as potentially important players in biological regulation. Here we discuss the evolving understanding of this new class of molecular regulators that has emerged from ongoing research, which continues to expand our databases of annotated lncRNAs and provide new insights into their physical properties, molecular mechanisms of action, and biological functions. We outline the current strategies and approaches that have been employed to identify and characterize lncRNAs, which have been instrumental in revealing their multifaceted roles ranging from cis- to trans-regulation of gene expression and from epigenetic modulation in the nucleus to posttranscriptional control in the cytoplasm. In addition, we highlight the molecular and biological functions of some of the best characterized lncRNAs in physiology and disease, especially those relevant to endocrinology, reproduction, metabolism, immunology, neurobiology, muscle biology, and cancer. Finally, we discuss the tremendous diagnostic and therapeutic potential of lncRNAs in cancer and other diseases.

Zhang B, Xing X, Li J, et al.
Comparative DNA methylome analysis of endometrial carcinoma reveals complex and distinct deregulation of cancer promoters and enhancers.
BMC Genomics. 2014; 15:868 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Aberrant DNA methylation is a hallmark of many cancers. Classically there are two types of endometrial cancer, endometrioid adenocarcinoma (EAC), or Type I, and uterine papillary serous carcinoma (UPSC), or Type II. However, the whole genome DNA methylation changes in these two classical types of endometrial cancer is still unknown.
RESULTS: Here we described complete genome-wide DNA methylome maps of EAC, UPSC, and normal endometrium by applying a combined strategy of methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylation-sensitive restriction enzyme digestion sequencing (MRE-seq). We discovered distinct genome-wide DNA methylation patterns in EAC and UPSC: 27,009 and 15,676 recurrent differentially methylated regions (DMRs) were identified respectively, compared with normal endometrium. Over 80% of DMRs were in intergenic and intronic regions. The majority of these DMRs were not interrogated on the commonly used Infinium 450K array platform. Large-scale demethylation of chromosome X was detected in UPSC, accompanied by decreased XIST expression. Importantly, we discovered that the majority of the DMRs harbored promoter or enhancer functions and are specifically associated with genes related to uterine development and disease. Among these, abnormal methylation of transposable elements (TEs) may provide a novel mechanism to deregulate normal endometrium-specific enhancers derived from specific TEs.
CONCLUSIONS: DNA methylation changes are an important signature of endometrial cancer and regulate gene expression by affecting not only proximal promoters but also distal enhancers.

Bundela S, Sharma A, Bisen PS
Potential therapeutic targets for oral cancer: ADM, TP53, EGFR, LYN, CTLA4, SKIL, CTGF, CD70.
PLoS One. 2014; 9(7):e102610 [PubMed] Free Access to Full Article Related Publications
In India, oral cancer has consistently ranked among top three causes of cancer-related deaths, and it has emerged as a top cause for the cancer-related deaths among men. Lack of effective therapeutic options is one of the main challenges in clinical management of oral cancer patients. We interrogated large pool of samples from oral cancer gene expression studies to identify potential therapeutic targets that are involved in multiple cancer hallmark events. Therapeutic strategies directed towards such targets can be expected to effectively control cancer cells. Datasets from different gene expression studies were integrated by removing batch-effects and was used for downstream analyses, including differential expression analysis. Dependency network analysis was done to identify genes that undergo marked topological changes in oral cancer samples when compared with control samples. Causal reasoning analysis was carried out to identify significant hypotheses, which can explain gene expression profiles observed in oral cancer samples. Text-mining based approach was used to detect cancer hallmarks associated with genes significantly expressed in oral cancer. In all, 2365 genes were detected to be differentially expressed genes, which includes some of the highly differentially expressed genes like matrix metalloproteinases (MMP-1/3/10/13), chemokine (C-X-C motif) ligands (IL8, CXCL-10/-11), PTHLH, SERPINE1, NELL2, S100A7A, MAL, CRNN, TGM3, CLCA4, keratins (KRT-3/4/13/76/78), SERPINB11 and serine peptidase inhibitors (SPINK-5/7). XIST, TCEAL2, NRAS and FGFR2 are some of the important genes detected by dependency and causal network analysis. Literature mining analysis annotated 1014 genes, out of which 841 genes were statistically significantly annotated. The integration of output of various analyses, resulted in the list of potential therapeutic targets for oral cancer, which included targets such as ADM, TP53, EGFR, LYN, CTLA4, SKIL, CTGF and CD70.

Chaligné R, Heard E
X-chromosome inactivation in development and cancer.
FEBS Lett. 2014; 588(15):2514-22 [PubMed] Related Publications
X-chromosome inactivation represents an epigenetics paradigm and a powerful model system of facultative heterochromatin formation triggered by a non-coding RNA, Xist, during development. Once established, the inactive state of the Xi is highly stable in somatic cells, thanks to a combination of chromatin associated proteins, DNA methylation and nuclear organization. However, sporadic reactivation of X-linked genes has been reported during ageing and in transformed cells and disappearance of the Barr body is frequently observed in cancer cells. In this review we summarise current knowledge on the epigenetic changes that accompany X inactivation and discuss the extent to which the inactive X chromosome may be epigenetically or genetically perturbed in breast cancer.

de Oliveira Georges JA, Vergani N, Fonseca SA, et al.
Aberrant patterns of X chromosome inactivation in a new line of human embryonic stem cells established in physiological oxygen concentrations.
Stem Cell Rev. 2014; 10(4):472-9 [PubMed] Related Publications
One of the differences between murine and human embryonic stem cells (ESCs) is the epigenetic state of the X chromosomes in female lines. Murine ESCs (mESCs) present two transcriptionally active Xs that will undergo the dosage compensation process of XCI upon differentiation, whereas most human ESCs (hESCs) spontaneously inactivate one X while keeping their pluripotency. Whether this reflects differences in embryonic development of mice and humans, or distinct culture requirements for the two kinds of pluripotent cells is not known. Recently it has been shown that hESCs established in physiological oxygen levels are in a stable pre-XCI state equivalent to that of mESCs, suggesting that culture in low oxygen concentration is enough to preserve that epigenetic state of the X chromosomes. Here we describe the establishment of two new lines of hESCs under physiological oxygen level and the characterization of the XCI state in the 46,XX line BR-5. We show that a fraction of undifferentiated cells present XIST RNA accumulation and single H3K27me foci, characteristic of the inactive X. Moreover, analysis of allele specific gene expression suggests that pluripotent BR-5 cells present completely skewed XCI. Our data indicate that physiological levels of oxygen are not sufficient for the stabilization of the pre-XCI state in hESCs.

Sato S, Maekawa R, Yamagata Y, et al.
Potential mechanisms of aberrant DNA hypomethylation on the x chromosome in uterine leiomyomas.
J Reprod Dev. 2014; 60(1):47-54 [PubMed] Free Access to Full Article Related Publications
We recently found that aberrant DNA hypomethylation is more common on the X chromosome than on other chromosomes in uterine leiomyomas by genome-wide DNA methylation profiling. To investigate the mechanism of aberrant hypomethylation on the X chromosome in uterine leiomyomas, we analyzed methylome and transcriptome data from three cases of leiomyomas and the adjacent myometrium. We found that eleven of the aberrantly hypomethylated genes on the X chromosome were common to the three cases. None of these 11 genes were transcriptionally upregulated in the leiomyoma. However, one of them, TSPYL2, was hypomethylated in 68% of multiple leiomyoma specimens. The incidence of aberrant hypomethylation of TSPYL2 was comparable to that of the MED12 mutation (68%), which is known to be detected at a high frequency in uterine leiomyomas. We also analyzed the aberration of the X chromosome inactivation (XCI) mechanism in uterine leiomyomas. Hypomethylation was not enriched in the imprinted genes, suggesting that dysfunction of polycomb repressive complexes is not involved in the aberrant hypomethylation on the X chromosome. The expression analysis of XCI-related genes revealed that the XIST and SATB1 expression was downregulated in 36% and 46% of 11 leiomyoma specimens, respectively, while the HNRNPU and SMCHD1 expression was not altered. In conclusion, the aberration of XCI-related genes such as SATB1 or XIST may be involved in aberrant hypomethylation on the X chromosome in a certain population of the patients with uterine leiomyomas. TSPYL2 of the aberrantly hypomethylated genes on the X chromosome can be used as a biomarker of uterine leiomyomas.

Salvador MA, Wicinski J, Cabaud O, et al.
The histone deacetylase inhibitor abexinostat induces cancer stem cells differentiation in breast cancer with low Xist expression.
Clin Cancer Res. 2013; 19(23):6520-31 [PubMed] Related Publications
PURPOSE: Cancer stem cells (CSC) are the tumorigenic cell population that has been shown to sustain tumor growth and to resist conventional therapies. The purpose of this study was to evaluate the potential of histone deacetylase inhibitors (HDACi) as anti-CSC therapies.
EXPERIMENTAL DESIGN: We evaluated the effect of the HDACi compound abexinostat on CSCs from 16 breast cancer cell lines (BCL) using ALDEFLUOR assay and tumorsphere formation. We performed gene expression profiling to identify biomarkers predicting drug response to abexinostat. Then, we used patient-derived xenograft (PDX) to confirm, in vivo, abexinostat treatment effect on breast CSCs according to the identified biomarkers.
RESULTS: We identified two drug-response profiles to abexinostat in BCLs. Abexinostat induced CSC differentiation in low-dose sensitive BCLs, whereas it did not have any effect on the CSC population from high-dose sensitive BCLs. Using gene expression profiling, we identified the long noncoding RNA Xist (X-inactive specific transcript) as a biomarker predicting BCL response to HDACi. We validated that low Xist expression predicts drug response in PDXs associated with a significant reduction of the breast CSC population.
CONCLUSIONS: Our study opens promising perspectives for the use of HDACi as a differentiation therapy targeting the breast CSCs and identified a biomarker to select patients with breast cancer susceptible to responding to this treatment.

Froberg JE, Yang L, Lee JT
Guided by RNAs: X-inactivation as a model for lncRNA function.
J Mol Biol. 2013; 425(19):3698-706 [PubMed] Free Access to Full Article Related Publications
The recent revolution in sequencing technology has helped to reveal a large transcriptome of long non-coding RNAs (lncRNAs). A major challenge in the years to come is to determine what biological functions, if any, they serve. Although the purpose of these transcripts is largely unknown at present, existing examples suggest that lncRNAs play roles in a wide variety of biological processes. Exemplary cases are lncRNAs within the X-inactivation center. Indeed, lncRNAs dominate control of random X-chromosome inactivation (XCI). The RNA-based regulatory mechanisms of XCI include recruitment of chromatin modifiers, formation of RNA-based subnuclear compartments, and regulation of transcription by antisense transcription. XCI and lncRNAs now also appear to be very relevant in the development and progression of cancer. This perspective focuses on new insights into lncRNA-dependent regulation of XCI, which we believe serve as paradigms for understanding lncRNA function more generally.

Shi X, Sun M, Liu H, et al.
Long non-coding RNAs: a new frontier in the study of human diseases.
Cancer Lett. 2013; 339(2):159-66 [PubMed] Related Publications
With the development of whole genome and transcriptome sequencing technologies, long noncoding RNAs (lncRNAs) have received increased attention. Multiple studies indicate that lncRNAs act not only as the intermediary between DNA and protein but also as important protagonists of cellular functions. LncRNAs can regulate gene expression in many ways, including chromosome remodeling, transcription and post-transcriptional processing. Moreover, the dysregulation of lncRNAs has increasingly been linked to many human diseases, especially in cancers. Here, we reviewed the rapidly advancing field of lncRNAs and described the relationship between the dysregulation of lncRNAs and human diseases, highlighting the specific roles of lncRNAs in human diseases.

Rinner B, Weinhaeusel A, Lohberger B, et al.
Chordoma characterization of significant changes of the DNA methylation pattern.
PLoS One. 2013; 8(3):e56609 [PubMed] Free Access to Full Article Related Publications
Chordomas are rare mesenchymal tumors occurring exclusively in the midline from clivus to sacrum. Early tumor detection is extremely important as these tumors are resistant to chemotherapy and irradiation. Despite continuous research efforts surgical excision remains the main treatment option. Because of the often challenging anatomic location early detection is important to enable complete tumor resection and to reduce the high incidence of local recurrences. The aim of this study was to explore whether DNA methylation, a well known epigenetic marker, may play a role in chordoma development and if hypermethylation of specific CpG islands may serve as potential biomarkers correlated with SNP analyses in chordoma. The study was performed on tumor samples from ten chordoma patients. We found significant genomic instability by Affymetrix 6.0. It was interesting to see that all chordomas showed a loss of 3q26.32 (PIK 3CA) and 3q27.3 (BCL6) thus underlining the potential importance of the PI3K pathway in chordoma development. By using the AITCpG360 methylation assay we elucidated 20 genes which were hyper/hypomethylated compared to normal blood. The most promising candidates were nine hyper/hypomethylated genes C3, XIST, TACSTD2, FMR1, HIC1, RARB, DLEC1, KL, and RASSF1. In summary, we have shown that chordomas are characterized by a significant genomic instability and furthermore we demonstrated a characteristic DNA methylation pattern. These findings add new insights into chordoma development, diagnosis and potential new treatment options.

Kitagawa M, Kotake Y, Ohhata T
Long non-coding RNAs involved in cancer development and cell fate determination.
Curr Drug Targets. 2012; 13(13):1616-21 [PubMed] Related Publications
The possible physiological significance of long non-coding RNAs (lncRNAs) has only recently been recognized. Technical innovations such as the super high-resolution tiling array and deep sequencing technology have indicated their importance. It has been proposed that lncRNAs such as HOTAIR are involved in the recruitment of chromatin modifiers to the target genes. The lncRNA ANRIL has been reported to be associated with a Polycomb complex, recruiting it to the target gene INK4 locus where it suppresses transcription via histone modification. Other lncRNAs such as Kcnq1ot1, AIR and Xist have also been found to recruit chromatin modifiers to their target loci. In this review, we discuss the function of lncRNAs such as HOTAIR, ANRIL, Kcnq1ot1, and Xist which recruit chromatin modifiers to target genes and discuss their involvement in cancer development and aggressiveness, and other cell fate determination.

Brim H, Lee E, Abu-Asab MS, et al.
Genomic aberrations in an African American colorectal cancer cohort reveals a MSI-specific profile and chromosome X amplification in male patients.
PLoS One. 2012; 7(8):e40392 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: DNA aberrations that cause colorectal cancer (CRC) occur in multiple steps that involve microsatellite instability (MSI) and chromosomal instability (CIN). Herein, we studied CRCs from AA patients for their CIN and MSI status.
EXPERIMENTAL DESIGN: Array CGH was performed on 30 AA colon tumors. The MSI status was established. The CGH data from AA were compared to published lists of 41 TSG and oncogenes in Caucasians and 68 cancer genes, proposed via systematic sequencing for somatic mutations in colon and breast tumors. The patient-by-patient CGH profiles were organized into a maximum parsimony cladogram to give insights into the tumors' aberrations lineage.
RESULTS: The CGH analysis revealed that CIN was independent of age, gender, stage or location. However, both the number and nature of aberrations seem to depend on the MSI status. MSI-H tumors clustered together in the cladogram. The chromosomes with the highest rates of CGH aberrations were 3, 5, 7, 8, 20 and X. Chromosome X was primarily amplified in male patients. A comparison with Caucasians revealed an overall similar aberration profile with few exceptions for the following genes; THRB, RAF1, LPL, DCC, XIST, PCNT, STS and genes on the 20q12-q13 cytoband. Among the 68 CAN genes, all showed some level of alteration in our cohort.
CONCLUSION: Chromosome X amplification in male patients with CRC merits follow-up. The observed CIN may play a distinctive role in CRC in AAs. The clustering of MSI-H tumors in global CGH data analysis suggests that chromosomal aberrations are not random.

Anguera MC, Sadreyev R, Zhang Z, et al.
Molecular signatures of human induced pluripotent stem cells highlight sex differences and cancer genes.
Cell Stem Cell. 2012; 11(1):75-90 [PubMed] Free Access to Full Article Related Publications
Although human induced pluripotent stem cells (hiPSCs) have enormous potential in regenerative medicine, their epigenetic variability suggests that some lines may not be suitable for human therapy. There are currently few benchmarks for assessing quality. Here we show that X-inactivation markers can be used to separate hiPSC lines into distinct epigenetic classes and that the classes are phenotypically distinct. Loss of XIST expression is strongly correlated with upregulation of X-linked oncogenes, accelerated growth rate in vitro, and poorer differentiation in vivo. Whereas differences in X-inactivation potential result in epigenetic variability of female hiPSC lines, male hiPSC lines generally resemble each other and do not overexpress the oncogenes. Neither physiological oxygen levels nor HDAC inhibitors offer advantages to culturing female hiPSC lines. We conclude that female hiPSCs may be epigenetically less stable in culture and caution that loss of XIST may result in qualitatively less desirable stem cell lines.

Okamoto K
Epigenetics: a way to understand the origin and biology of testicular germ cell tumors.
Int J Urol. 2012; 19(6):504-11 [PubMed] Related Publications
Testicular germ cell tumors are neoplasms carrying two unique features. First, testicular germ cell tumors have a pluripotential nature and show protean histology ranging from that of germ cells to embryonal and differentiated somatic cells. Therefore, testicular germ cell tumors are interesting resources positioned at a crossroad in developmental and neoplastic processes. The second unique feature of testicular germ cell tumors is their exquisite sensitivity to cisplatin-based chemotherapy. This review summarizes recent research progress in the epigenetics of testicular germ cell tumors in an attempt to explain the abovementioned biological and clinical characteristics of testicular germ cell tumors.

Wang RT, Ahn S, Park CC, et al.
Effects of genome-wide copy number variation on expression in mammalian cells.
BMC Genomics. 2011; 12:562 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: There is only a limited understanding of the relation between copy number and expression for mammalian genes. We fine mapped cis and trans regulatory loci due to copy number change for essentially all genes using a human-hamster radiation hybrid (RH) panel. These loci are called copy number expression quantitative trait loci (ceQTLs).
RESULTS: Unexpected findings from a previous study of a mouse-hamster RH panel were replicated. These findings included decreased expression as a result of increased copy number for 30% of genes and an attenuated relationship between expression and copy number on the X chromosome suggesting an Xist independent form of dosage compensation. In a separate glioblastoma dataset, we found conservation of genes in which dosage was negatively correlated with gene expression. These genes were enriched in signaling and receptor activities. The observation of attenuated X-linked gene expression in response to increased gene number was also replicated in the glioblastoma dataset. Of 523 gene deserts of size > 600 kb in the human RH panel, 325 contained trans ceQTLs with -log10 P > 4.1. Recently discovered genes, ultra conserved regions, noncoding RNAs and microRNAs explained only a small fraction of the results, suggesting a substantial portion of gene deserts harbor as yet unidentified functional elements.
CONCLUSION: Radiation hybrids are a useful tool for high resolution mapping of cis and trans loci capable of affecting gene expression due to copy number change. Analysis of two independent radiation hybrid panels show agreement in their findings and may serve as a discovery source for novel regulatory loci in noncoding regions of the genome.

Ushida H, Kawakami T, Minami K, et al.
Methylation profile of DNA repetitive elements in human testicular germ cell tumor.
Mol Carcinog. 2012; 51(9):711-22 [PubMed] Related Publications
Testicular germ cell tumors (TGCTs) have a unique epigenetic profile distinct from that of other types of cancer. To further evaluate epigenetics of TGCTs, this study examines DNA methylation patterns of DNA repetitive elements in TGCTs. Bisulfite genomic sequencing and combined bisulfite restriction analysis (COBRA) were used to analyze the methylation patterns of DNA repetitive elements (LINE1 and Alu repeats) in embryonal carcinoma (EC) derived cell lines, primary TGCT tissues, noncancerous testicular tissues adjacent to TGCTs and cancer cells derived from somatic tissues (testicular malignant lymphoma tissues and renal cell carcinoma cell lines). Through both bisulfite genomic sequencing and COBRA, LINE1 was extensively hypomethylated in both seminomatous and nonseminomatous TGCT tissues as well as EC cell lines. We studied two Alu repeats locating in the 5' end of E-cadherin and XIST by bisulfite genomic sequencing. These two Alu elements were extensively hypomethylated in seminomatous TGCTs, but methylated in nonseminomatous TGCTs, including two EC derived cell lines. This increased unmethylated profile in seminomatous TGCTs was observed also by COBRA for Alu repeats. Although partial demethylation of DNA repetitive elements was observed in cancer cells of somatic tissue origin, the degree of demethylation was more pronounced in TGCTs than in cancer cells of somatic tissue origin. We observed abnormal demethylation of DNA repetitive elements in some of the tissues adjacent to TGCTs. The results indicate that the underlying mechanisms to undergo or maintain demethylation of DNA repetitive sequences differ between TGCTs and cancer cells of somatic tissue origin.

Maekawa R, Yagi S, Ohgane J, et al.
Disease-dependent differently methylated regions (D-DMRs) of DNA are enriched on the X chromosome in uterine leiomyoma.
J Reprod Dev. 2011; 57(5):604-12 [PubMed] Related Publications
Uterine leiomyoma is the most common benign tumor in women. Although responsible gene mutations have not been found in leiomyomas, they represent a progressive disease with irreversible symptoms. To characterize epigenetic features of uterine leiomyomas, the DNA methylation status of a paired sample of leiomyoma and normal myometrium was subjected to a microarray-based DNA methylation analysis with restriction tag-mediated amplification (D-REAM). In the leiomyoma, we identified an aberrant DNA methylation status for 463 hypomethylated and 318 hypermethylated genes. Although these changes occurred on all chromosomes, aberrantly hypomethylated genes were preferentially located on the X chromosome. Using paired samples of normal myometrium and leiomyoma from 6 hysterectomy patients, methylation-sensitive quantitative real-time PCR revealed 14 shared X chromosome genes with an abnormal DNA hypomethylation status (FAM9A, CPXCR1, CXORF45, TAF1, NXF5, VBP1, GABRE, DDX53, FHL1, BRCC3, DMD, GJB1, AP1S2 and PCDH11X) and one hypermethylated locus (HDAC8). Expression of XIST, which is involved in X chromosome inactivation, was equivalent in the normal myometrium and leiomyoma, indicating that the epigenetic abnormality on the X chromosome did not result from aberration of XIST gene expression. Based on these data, a unique epigenetic signature for uterine leiomyomas has emerged. The 14 hypomethylated and one hypermethylated loci provide valuable biomarkers for understanding the molecular pathogenesis of leiomyoma.

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