Transcribed Ultraconserved Regions in Cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Gibert MK
PROVIDER: S-EPMC9139194 | biostudies-literature | 2022 May
REPOSITORIES: biostudies-literature
Publications
Transcribed Ultraconserved Regions in Cancer.
Gibert Myron K MK Sarkar Aditya A Chagari Bilhan B Roig-Laboy Christian C Saha Shekhar S Bednarek Sylwia S Kefas Benjamin B Hanif Farina F Hudson Kadie K Dube Collin C Zhang Ying Y Abounader Roger R
Cells 20220519 10
Transcribed ultraconserved regions are putative lncRNA molecules that are transcribed from DNA that is 100% conserved in human, mouse, and rat genomes. This is notable, as lncRNAs are typically poorly conserved. TUCRs remain very understudied in many diseases, including cancer. In this review, we summarize the current literature on TUCRs in cancer with respect to expression deregulation, functional roles, mechanisms of action, and clinical perspectives. ...[more]
Similar Datasets
Project description:Ultraconserved regions (UCRs) are 481 genome segments, with length longer than 200 bp, that are 100% conserved among humans, mice, and rats. The majority of UCRs are transcriptionally active (T-UCRs) as many of them produce non-coding RNAs. In a previous study, we evaluated the expression level of T-UCRs in breast cancer (BC) patients and found that 63% of transcripts correlated with some clinical and/or molecular parameter of BC. In this study, we delved into the expression levels of 12 T-UCRs and correlated them with clinicopathological parameters, immunohistochemical markers, and overall survival in two breast cancer cohorts: TCGA and Brazilian patients. We found that uc.268 is more expressed in TCGA patients under 40 years of age, associated with progesterone receptor (PR) and estrogen receptor (ER), and its high expression is found in luminal A. Lower uc.84 and uc.376 were respectively observed in metastatic and stage IV tumors associated with good prognostic in luminal B. Moreover, uc.84 was only related to the HER2+, while uc.376 was related to ER+ and PR+, and HER2+. A panel composed of uc.147, uc.271, and uc.427 distinguished luminal A from triple negative patients with an AUC of 0.9531 (sensitivity 92.19% and specificity 86.76%). These results highlight the potential role of T-UCRs in BC and provide insights into the potential application of T-UCRs as biomarkers.
| S-EPMC8961524 | biostudies-literature
Project description:The ultraconserved regions (UCRs) are 481 genomic elements, longer than 200 bp, 100% conserved in human, mouse, and rat genomes. Usually, coding regions are more conserved, but more than 80% of UCRs are either intergenic or intronic, and many of them produce long non-coding RNAs (lncRNAs). Recently, the deregulated expression of transcribed UCRs (T-UCRs) has been associated with pathological conditions. But, differently from many lncRNAs with recognized crucial effects on malignant cell processes, the role of T-UCRs in the control of cancer cell networks is understudied. Furthermore, the potential utility of these molecules as molecular markers is not clear. Based on this information, the present review aims to organize information about T-UCRs with either oncogenic or tumor suppressor role associated with cancer cell signaling, and better describe T-UCRs with potential utility as prognosis markers. Out of 481 T-UCRs, 297 present differential expression in cancer samples, 23 molecules are associated with tumorigenesis processes, and 12 have more clear potential utility as prognosis markers. In conclusion, T-UCRs are deregulated in several tumor types, highlighted as important molecules in cancer networks, and with potential utility as prognosis markers, although further investigation for translational medicine is still needed.
| S-EPMC9829027 | biostudies-literature
Project description:Emerging evidence indicates that 481 regions of the genome (>200 bp) that actively transcribe noncoding RNAs shows 100% homology between humans, rats and mice. These transcribed ultraconserved regions (T-UCRs) are thought to control the essential regulatory functions basic for life in rodents and mammals. Using microarray analysis, we presently show that 107 T-UCRs are actively expressed in adult rat cerebral cortex. They are grouped into intragenic (61) and intergenic (46) based on their genic location. Interestingly, 10 T-UCRs are expressed at unusually high levels in cerebral cortex. Additionally, many T-UCRs also showed cogenic expression. We further analyzed the correlation of intragenic T-UCRs with their host protein coding genes. Surprisingly, most of the expressed intragenic T-UCRs (54 out of 61) displayed a negative correlation with their host gene expression. T-UCRs are thought to control the splicing and transcription of the protein-coding genes that host them and flank them. Bioinformatics analysis indicated that the protein products of majority of these genes are nuclear in localization, share protein domains and are involved in the regulation of diverse biological and molecular functions including metabolism, development, cell cycle, binding and transcription factor regulation. In conclusion, this is the first study to shows that many T-UCRs are expressed in rodent brain and they might play a role in physiological brain functions.
| S-EPMC4286335 | biostudies-literature
Project description:Although only 1.5% of the human genome appears to code for proteins, much effort in cancer research has been devoted to this minimal fraction of our DNA. However, the last few years have witnessed the realization that a large class of non-coding RNAs (ncRNAs), named microRNAs, contribute to cancer development and progression by acting as oncogenes or tumor suppressor genes. Recent studies have also shown that epigenetic silencing of microRNAs with tumor suppressor features by CpG island hypermethylation is a common hallmark of human tumors. Thus, we wondered whether there were other ncRNAs undergoing aberrant DNA methylation-associated silencing in transformed cells. We focused on the transcribed-ultraconserved regions (T-UCRs), a subset of DNA sequences that are absolutely conserved between orthologous regions of the human, rat and mouse genomes and that are located in both intra- and intergenic regions. We used a pharmacological and genomic approach to reveal the possible existence of an aberrant epigenetic silencing pattern of T-UCRs by treating cancer cells with a DNA-demethylating agent followed by hybridization to an expression microarray containing these sequences. We observed that DNA hypomethylation induces release of T-UCR silencing in cancer cells. Among the T-UCRs that were reactivated upon drug treatment, Uc.160+, Uc283+A and Uc.346+ were found to undergo specific CpG island hypermethylation-associated silencing in cancer cells compared with normal tissues. The analysis of a large set of primary human tumors (n=283) demonstrated that hypermethylation of the described T-UCR CpG islands was a common event among the various tumor types. Our finding that, in addition to microRNAs, another class of ncRNAs (T-UCRs) undergoes DNA methylation-associated inactivation in transformed cells supports a model in which epigenetic and genetic alterations in coding and non-coding sequences cooperate in human tumorigenesis.
| S-EPMC3007676 | biostudies-literature
Project description:Background and purposeHuman and rodent genomes diverged ≈75 million years ago. However, 481 regions of their genomes (200-779 nucleotide each) remained absolutely conserved and form noncoding RNAs known as transcribed ultraconserved regions (T-UCRs). The functional significance of T-UCRs is not apparent, but their altered expression is associated with many diseases, and thus thought to be critical for life. We presently investigated the poststroke temporal changes in the expression of T-UCRs with potential functional significance.MethodsMale, spontaneously hypertensive rats were subjected to transient middle cerebral artery occlusion. Expression profile of T-UCRs was determined at 3, 6, and 12 hours of reperfusion using microarrays and real-time polymerase chain reaction in the peri-infarct cortex. The putative functional significance of stroke-responsive T-UCRs was identified by bioinformatics.ResultsIschemia altered expression of 69 T-UCRs at ≥1 time points of reperfusion compared with sham. Poststroke expression of the intragenic T-UCRs is independent of the expression of their parent gene mRNAs. Bioinformatics showed that the upstream/downstream and the parent genes of the T-UCRs modulate several biological and molecular functions, including metabolism, response to stimuli, cell communication, protein and nucleic acid binding.ConclusionsThis first report shows that ischemic stroke temporally alters the noncoding ultraconserved RNAs in spontaneously hypertensive rats, but their functional significance is yet to be evaluated.
| S-EPMC5875717 | biostudies-literature
Project description:Ultraconserved regions (UCRs) are 481 genomic sequences with 100% identity across humans, rats, and mice. Increasing evidence suggests that non-coding RNAs transcribed from UCRs are involved in various diseases, especially cancers. The human transformer 2β gene (TRA2B) encodes a UCR (uc.138) that spans exon 2 and its neighboring introns. TRA2B4 RNA is the only transcript that contains the whole exon 2 among five spliced TRA2B RNA variants (TRA2B1-5). TRA2B4 is upregulated in colon cancer cell lines, although it is not translated to Tra2β protein because of its nuclear retention. Nevertheless, the clinical significance and biological functions of uc.138 in colon cancer cells remain unclear. In this study, RNA in situ hybridization showed that TRA2B4 was predominantly overexpressed in the nucleus of colon adenocarcinoma and adenoma. Overexpression of TRA2B4 in colon cancer HCT116 cells promoted cell proliferation by changing the expression of G2/M-related cell cycle regulators. Moreover, TRA2B4 increased migration and cell viability in a uc.138 sequence-dependent manner. TRA2B4 significantly enhanced tumorigenesis in vivo. Taken together, uc.138 encoded in TRA2B4 plays an oncogenic role in tumor progression and may become a potential biomarker and therapeutic target in colon cancer.
| S-EPMC8060298 | biostudies-literature
Project description:Ultraconserved regions (UCRs) are segments of the human genome located in both intragenic and intergenic regions that are highly conserved in orthologous regions of the human, rat, and mouse genomes. Their transcriptional products, called T-UCRs, compose a new category of long noncoding RNA (lncRNAs). Most importantly, recent data suggests that T-UCRs are altered at the transcriptional level in human tumorigenesis and the aberrant T-UCRs expression profiles can be used to differentiate human cancer types. MicroRNAs and other types of non-codingRNAs have been shown to greatly contribute at biological function of cancer and are increasingly being used to help prognosticate patients with bladder cancer, this is not yet the case for T-UCRs. The presence and the roles for T-UCRs across different species is largely unknown rendering their investigation particularly important in our understanding the biology of cancer. Using genome-wide profiling, we identified 293 T-UCRs that were dysregulated in bladder tumor (n = 24) but not normal bladder tissues (n = 17) samples. The greatest change in expression was for the ultraconserved element 8 (uc.8+), whose expression significantly increased (6.7 fold; P = 0.001) in bladder cancer tissues. Dysregulated expression was validated for several T-UCRs in 60 patients and 16 healthy donors. We found that T-UCR 8+ acts as a natural decoy RNA for miR-596 in patients and bladder cancer cells. As a result, expression of matrix metallopeptidase 9, a direct target of this microRNA, was upregulated, thereby promoting cancer cell growth, migration, and invasion. We also observed that mir-596 mediated a network of interactions among uc.8+, uc.339+, uc.195+, and uc.388+, which appeared to be dysregulated in bladder tumors. Transcribed ultraconserved ncRNAs provide an evolutionarily-conserved regulatory layer that modulates miRNA levels, and opens up the possibility for the development of useful markers for diagnosis and prognosis, as well as for the development of new RNA-based cancer therapies.
2016-03-23 | GSE68594 | GEO
Project description:BackgroundUltraconserved regions (UCR) are genomic segments of more than 200 base pairs that are evolutionarily conserved among mammalian species. They are thought to have functions as transcriptional enhancers and regulators of alternative splicing. Recently, it was shown that numerous RNAs are transcribed from these regions. These UCR-encoded transcripts (ucRNAs) were found to be expressed in a tissue- and disease-specific manner and may interfere with the function of other RNAs through RNA: RNA interactions. We hypothesized that ucRNAs have unidentified roles in the pathogenesis of human prostate cancer. In a pilot study, we examined ucRNA expression profiles in human prostate tumors.MethodsUsing a custom microarray with 962 probesets representing sense and antisense sequences for the 481 human UCRs, we examined ucRNA expression in resected, fresh-frozen human prostate tissues (57 tumors, 7 non-cancerous prostate tissues) and in cultured prostate cancer cells treated with either epigenetic drugs (the hypomethylating agent, 5-Aza 2'deoxycytidine, and the histone deacetylase inhibitor, trichostatin A) or a synthetic androgen, R1881. Expression of selected ucRNAs was also assessed by qRT-PCR and NanoString®-based assays. Because ucRNAs may function as RNAs that target protein-coding genes through direct and inhibitory RNA: RNA interactions, computational analyses were applied to identify candidate ucRNA:mRNA binding pairs.ResultsWe observed altered ucRNA expression in prostate cancer (e.g., uc.106+, uc.477+, uc.363 + A, uc.454 + A) and found that these ucRNAs were associated with cancer development, Gleason score, and extraprostatic extension after controlling for false discovery (false discovery rate < 5% for many of the transcripts). We also identified several ucRNAs that were responsive to treatment with either epigenetic drugs or androgen (R1881). For example, experiments with LNCaP human prostate cancer cells showed that uc.287+ is induced by R1881 (P < 0.05) whereas uc.283 + A was up-regulated following treatment with combined 5-Aza 2'deoxycytidine and trichostatin A (P < 0.05). Additional computational analyses predicted RNA loop-loop interactions of 302 different sense and antisense ucRNAs with 1058 different mRNAs, inferring possible functions of ucRNAs via direct interactions with mRNAs.ConclusionsThis first study of ucRNA expression in human prostate cancer indicates an altered transcript expression in the disease.
| S-EPMC3626580 | biostudies-literature
Project description:Ultraconserved regions (UCRs) are DNA segments of longer than 200 bp in length that are completely conserved between human, rat, and mouse genomes. Recent studies have shown that UCRs are frequently located at fragile sites involved in cancers, and their levels of transcription can be altered during human tumorigenesis. We systematically evaluated 14 common single-nucleotide polymorphisms (SNPs) within UCRs in three cohorts of prostate cancer patients, to test the hypothesis that these UCR SNPs might influence clinical outcomes. Examination using multivariate analysis adjusted for known clinicopathologic factors found association between rs8004379 and recurrence in localized disease [hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.41-0.91, P = 0.015], which was confirmed in the replication set (HR 0.70, 95% CI 0.51-0.96, P = 0.027). Remarkably, a consistent association of rs8004379 with a decreased risk for prostate cancer-specific mortality was also observed in the advanced prostate cancer patient group (HR 0.48, 95% CI 0.32-0.70, P < 0.001). Additional in silico analysis suggests that rs8004379 tends to affect NPAS3 expression, which in turn was found to be correlated with patient prognosis. In conclusion, our findings suggest that SNPs within UCRs may be valuable prognostic biomarkers for assessing prostate cancer treatment response and survival.
| S-EPMC4763269 | biostudies-literature
Project description:Barrett's esophagus (BE) involves a metaplastic replacement of native esophageal squamous epithelium (Sq) by columnar-intestinalized mucosa, and it is the main risk factor for Barrett-related adenocarcinoma (BAc). Ultra-conserved regions (UCRs) are a class non-coding sequences that are conserved in humans, mice and rats. More than 90% of UCRs are transcribed (T-UCRs) in normal tissues, and are altered at transcriptional level in tumorigenesis. To identify the T-UCR profiles that are dysregulated in Barrett's mucosa transformation, microarray analysis was performed on a discovery set of 51 macro-dissected samples obtained from 14 long-segment BE patients. Results were validated in an independent series of esophageal biopsy/surgery specimens and in two murine models of Barrett's esophagus (i.e. esophagogastric-duodenal anastomosis). Progression from normal to BE to adenocarcinoma was each associated with specific and mutually exclusive T-UCR signatures that included up-regulation of uc.58-, uc.202-, uc.207-, and uc.223- and down-regulation of uc.214+. A 9 T-UCR signature characterized BE versus Sq (with the down-regulation of uc.161-, uc.165-, and uc.327-, and the up-regulation of uc.153-, uc.158-, uc.206-, uc.274-, uc.472-, and uc.473-). Analogous BE-specific T-UCR profiles were shared by human and murine lesions. This study is the first demonstration of a role for T-UCRs in the transformation of Barrett's mucosa.
| S-EPMC4196192 | biostudies-literature