Transcribed Ultraconserved Regions in Cancer

Gibert, Myron; Sarkar, Aditya; Chagari, Bilhan; Roig-Laboy, Christian; Saha, Shekhar; Bednarek, Sylwia; Kefas, Benjamin; Hanif, Farina; Hudson, Kadie; Dube, Collin; Zhang, Ying; Abounader, Roger

doi:10.3390/cells11101684

Cited by 10 publications

(19 citation statements)

References 84 publications

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“…Since TUCRs are expected to be resistant to variation [2], we characterized the overlap of current dbSNP (build 156) single nucleotide polymorphism (SNP) annotations to the lifted over hg38 TUCR genomic coordinates. We found that TUCRs overlap with fewer SNPs than protein coding genes and non-coding RNAs, demonstrating that they are more resistant to variation (Figure 1E).…”

Section: Resultsmentioning

confidence: 99%

“…Because of their ultra-conservation and their deregulation, it is believed that TUCRs may have important regulatory roles in cancer. [2][3][4][5][6][7][8][9][10][11] About ~90% of the genome is transcribed, but only ~2 percent of the transcriptome is then translated. The remainder of the transcriptome is made up of non-coding elements that serve key regulatory roles.…”

Section: Introductionmentioning

confidence: 99%

“…[2] Very little is known about TUCRs. [2] In particular, the literature elucidating the expressions, functions, and mechanisms of action of TUCRs in glioblastoma (GBM) and low-grade glioma (LGG) is nonexistent. GBM and LGG represent over 80% of primary malignant brain tumors in humans, of which GBM is the deadliest, with a median survival of approximately 15 months.…”

Section: Introductionmentioning

confidence: 99%

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A comprehensive analysis of Transcribed Ultra Conserved Regions uncovers important regulatory functions of novel non-coding transcripts in gliomas

Gibert,

Zhang,

Saha

et al. 2023

Preprint

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Transcribed Ultra-Conserved Regions (TUCRs) represent a severely understudied class of putative non-coding RNAs (ncRNAs) that are 100% conserved across multiple species. We performed the first-ever analysis of TUCRs in glioblastoma (GBM) and low-grade gliomas (LGG). We leveraged large human datasets to identify the genomic locations, chromatin accessibility, transcription, differential expression, correlation with survival, and predicted functions of all 481 TUCRs, and identified TUCRs that are relevant to glioma biology. Of these, we investigated the expression, function, and mechanism of action of the most highly upregulated intergenic TUCR, uc.110, identifying it as a new oncogene. Uc.110 was highly overexpressed in GBM and LGG, where it promoted malignancy and tumor growth. Uc.110 activated the WNT pathway by upregulating the expression of membrane frizzled-related protein, by sponging the tumor suppressor miR-544. This pioneering study shows important roles for TUCRs in gliomas and provides an extensive database and novel methods for future TUCR research.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A comprehensive analysis of Transcribed Ultra Conserved Regions uncovers important regulatory functions of novel non-coding transcripts in gliomas

Gibert,

Zhang,

Saha

et al. 2023

Preprint

Self Cite

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“…Histone markers, including H3K27ac, H3K4me1, H3K4me1, and H3K9ac, are important modifications that are associated with the dysregulation of many genes that play important roles in cancer development and progression (Kurdistani, 2007). Transcribed regions have diverse transcripts that impact cancer initiation and progression through several mechanisms of action (Gibert et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

A genome-wide cross-cancer meta-analysis highlights the shared genetic links of five solid cancers

et al. 2023

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Breast, ovarian, prostate, lung, and head/neck cancers are five solid cancers with complex interrelationships. However, the shared genetic factors of the five cancers were often revealed either by the combination of individual genome-wide association study (GWAS) approach or by the fixed-effect model-based meta-analysis approach with practically impossible assumptions. Here, we presented a random-effect model-based cross-cancer meta-analysis framework for identifying the genetic variants jointly influencing the five solid cancers. A comprehensive genetic correlation analysis (genome-wide, partitioned, and local) approach was performed by using GWAS summary statistics of the five cancers, and we observed three cancer pairs with significant genetic correlation: breast–ovarian cancer (rg = 0.221, p = 0.0003), breast–lung cancer (rg = 0.234, p = 7.6 × 10−6), and lung–head/neck cancer (rg = 0.652, p = 0.010). Furthermore, a random-effect model-based cross-trait meta-analysis was conducted for each significant cancer pair, and we found 27 shared genetic loci between breast and ovarian cancers, 18 loci between breast and lung cancers, and three loci between lung and head/neck cancers. Functional analysis indicates that the shared genes are enriched in human T-cell leukemia virus 1 infection (HTLV-1) and antigen processing and presentation (APP) pathways. Our study investigates the shared genetic links across five solid cancers and will help to reveal their potential molecular mechanisms.

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“…ncRNAs (including T‐UCRs) can interact with and regulate each other through distinct molecular mechanisms generating a complex network including different species of RNAs 44 . Interplay between TUCRs and other lncRNAs and miRNAs, and the importance of such crosstalk during the tumorigenesis, provides new insight into the regulatory mechanisms underlying several ncRNA classes in cancer, 45 as previous reports have discovered that T‐UCRs are regulated by mRNAs and miRNAs 16,46 . Thus far, no comprehensive network construction has been reported including all T‐UCRs along with potential associated miRNAs, and mRNAs in GC.…”

Section: Discussionmentioning

confidence: 99%

Construction of a three‐component regulatory network of transcribed ultraconserved regions for the identification of prognostic biomarkers in gastric cancer

Khalafiyan

Emadi‐Baygi

Wolfien

et al. 2023

J of Cellular Biochemistry

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Altered expression and functional roles of the transcribed ultraconserved regions (T-UCRs), as genomic sequences with 100% conservation between the genomes of human, mouse, and rat, in the pathophysiology of neoplasms has already been investigated. Nevertheless, the relevance of the functions for T-UCRs in gastric cancer (GC) is still the subject of inquiry. In the current study, we first used a genome-wide profiling approach to analyze the expression of T-UCRs in GC patients. Then, we constructed a threecomponent regulatory network and investigated potential diagnostic and prognostic values of the T-UCRs. The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) dataset was used as a resource for the RNA-sequencing data. FeatureCounts was utilized to quantify the number of reads mapped to each T-UCR. Differential expression analysis was then conducted using DESeq2. In the following, interactions between T-UCRs, microRNAs (miRNAs), and messenger RNAs (mRNAs) were combined into a three-component network. Enrichment analyses were performed and a protein-protein interaction (PPI) network was constructed. The R Survival package was utilized to identify survival-related significantly differentially expressed T-UCRs (DET-UCRs). Using an in-house cohort of GC tissues, expression of two DET-UCRs was furthermore experimentally verified. Our results showed that several T-UCRs were dysregulated in TCGA-STAD tumoral samples compared to nontumoral counterparts. The three-component network was constructed which composed of DET-UCRs, miRNAs, and mRNAs nodes. Functional enrichment and PPI network analyses revealed important enriched signaling pathways and gene ontologies such as "pathway in cancer" and regulation of cell proliferation and apoptosis. Five T-UCRs were significantly correlated with the overall survival of GC patients. While no expression of uc.232 was observed in our in-house cohort of GC tissues, uc.343 showed an increased expression, although not statistically significant, in gastric tumoral tissues. The constructed three-component regulatory network of

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Transcribed Ultraconserved Regions in Cancer

Cited by 10 publications

References 84 publications

A comprehensive analysis of Transcribed Ultra Conserved Regions uncovers important regulatory functions of novel non-coding transcripts in gliomas

A comprehensive analysis of Transcribed Ultra Conserved Regions uncovers important regulatory functions of novel non-coding transcripts in gliomas

A genome-wide cross-cancer meta-analysis highlights the shared genetic links of five solid cancers

Construction of a three‐component regulatory network of transcribed ultraconserved regions for the identification of prognostic biomarkers in gastric cancer

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