Pseudogene-Derived lncRNAs and Their miRNA Sponging Mechanism in Human Cancer.
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ABSTRACT:
SUBMITTER: Lou W
PROVIDER: S-EPMC7058547 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
Pseudogene-Derived lncRNAs and Their miRNA Sponging Mechanism in Human Cancer.
Lou Weiyang W Ding Bisha B Fu Peifen P
Frontiers in cell and developmental biology 20200228
Pseudogenes, abundant in the human genome, are traditionally considered as non-functional "junk genes." However, recent studies have revealed that pseudogenes act as key regulators at DNA, RNA or protein level in diverse human disorders (including cancer), among which pseudogene-derived long non-coding RNA (lncRNA) transcripts are extensively investigated and has been reported to be frequently dysregulated in various types of human cancer. Growing evidence demonstrates that pseudogene-derived ln ...[more]
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Project description:Pseudogene-derived transcripts, especially those barely transcribed in normal tissues, have been regarded as a kind of non-coding RNAs, and present potential functions in tumorigenicity and tumor development in human beings. However, their exact effects on hepatocellular carcinoma (HCC) remain largely unknown. On basis of our previous research and the constructed online database for the non-coding RNAs related to HCC, a series of pseudogene transcripts have been discovered, and SNRPFP1, the homologous pseudogene of SNRPF, was found to produce an anomalously high expression long non-coding RNA in HCC. In this study, we validated the expression of the SNRPFP1 transcript in both HCC tissues and cell lines. The adverse correlation between SNRPFP1 expression and patients' outcomes was observed. And depletion of SNRPF1 in HCC cells significantly suppressed cell proliferation and apoptosis resistance. Meanwhile, the motility of HCC cells was potently impaired. Interestingly, miR-126-5p, one of the tumor-suppressive genes commonly decreased in HCC, was found negatively expressed and correlated with SNRPF1, and a specific region of SNRPF1 transcript is directly binding to miR-126-5p in a molecular sponge way. The rescue experiment by knock-out miR-126-5p significantly reversed the cell growth suppression and a higher ratio of cell apoptosis induced by SNRPF1 depletion. Lastly, we concluded that SNRPF1 is a pseudogene active in HCC, and its abnormally over-expressed transcript is a strong promoter of HCC cell progress in vitro by sponging miR-126-5p. We believe that the findings in this study provide new strategies for HCC prevention and therapeutic treatment.
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Project description:Thousands of pseudogenes exist in the human genome and many are transcribed, but their functional potential remains elusive and understudied. To explore these issues systematically, we first developed a computational pipeline to identify transcribed pseudogenes from RNA-Seq data. Applying the pipeline to datasets from 16 distinct normal human tissues identified ∼ 3,000 pseudogenes that could produce non-coding RNAs in a manner of low abundance but high tissue specificity under normal physiological conditions. Cross-tissue comparison revealed that the transcriptional profiles of pseudogenes and their parent genes showed mostly positive correlations, suggesting that pseudogene transcription could have a positive effect on the expression of their parent genes, perhaps by functioning as competing endogenous RNAs (ceRNAs), as previously suggested and demonstrated with the PTEN pseudogene, PTENP1. Our analysis of the ENCODE project data also found many transcriptionally active pseudogenes in the GM12878 and K562 cell lines; moreover, it showed that many human pseudogenes produced small RNAs (sRNAs) and some pseudogene-derived sRNAs, especially those from antisense strands, exhibited evidence of interfering with gene expression. Further integrated analysis of transcriptomics and epigenomics data, however, demonstrated that trimethylation of histone 3 at lysine 9 (H3K9me3), a posttranslational modification typically associated with gene repression and heterochromatin, was enriched at many transcribed pseudogenes in a transcription-level dependent manner in the two cell lines. The H3K9me3 enrichment was more prominent in pseudogenes that produced sRNAs at pseudogene loci and their adjacent regions, an observation further supported by the co-enrichment of SETDB1 (a H3K9 methyltransferase), suggesting that pseudogene sRNAs may have a role in regional chromatin repression. Taken together, our comprehensive and systematic characterization of pseudogene transcription uncovers a complex picture of how pseudogene ncRNAs could influence gene and pseudogene expression, at both epigenetic and post-transcriptional levels.
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Project description:Pseudogenes, non-coding homologs of protein-coding genes, were once considered non-functional evolutional relics. Recent studies have shown that pseudogene transcripts can regulate their parental transcripts by sequestering shared microRNAs, thus acting as competing endogenous RNAs (ceRNAs). In this study, we utilize an unbiased screen to identify the ferritin heavy chain 1 (FTH1) transcript and multiple FTH1 pseudogenes as targets of several oncogenic miRNAs in prostate cancer. We characterize the critical role of this FTH1 gene:pseudogene:microRNA network in regulating tumorigenesis in prostate cancer, and show that impairing microRNA binding and subsequent ceRNA crosstalk results in complete phenotype rescue. Our results also demonstrate that pseudogenes are able to regulate intracellular iron levels, which are crucial for multiple physiological and pathophysiological processes. In summary, we describe a novel and extensive gene:pseudogene ceRNA network comprising multiple microRNAs and multiple pseudogenes derived from a single parental gene, which regulates iron storage and tumorigenesis in prostate cancer.
2017-07-26 | GSE101837 | GEO
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Project description:Pseudogenes are an integral component of the human genome. Little attention, however, has so far been paid to the phenomenon that some pseudogenes are transcriptionally active. Recently, we demonstrated that the human ortholog of the rodent testis-specific ATP-binding cassette (ABC) transporter Abca17 is a ubiquitously transcribed pseudogene (ABCA17P). The aim of the present study was to establish a complete inventory of all ABC transporter pseudogenes in the human genome and to identify transcriptionally active ABC transporter pseudogenes. Moreover, we tested the hypothesis that a regulatory interdependency exists between ABC transporter pseudogenes and their parental protein coding equivalents.Systematic bioinformatic analysis revealed the existence of 22 ABC transporter pseudogenes within the human genome. We identified two clusters on chromosomes 15 and 16, respectively, which harbor almost half of all pseudogenes (n = 10). Available information from EST and mRNA databases and RT-PCR expression profiling indicate that a large portion of the ABC transporter pseudogenes (45%, n = 10) are transcriptionally active and some of them are expressed as alternative splice variants. We demonstrate that both pseudogenes of the pseudoxanthoma elasticum gene ABCC6, ABCC6P1 and ABCC6P2, are transcribed. ABCC6P1 and ABCC6 possess near-identical promoter sequences and their tissue-specific expression profiles are strikingly similar raising the possibility that they form a gene-pseudogene dual transcription unit. Intriguingly, targeted knockdown of the transcribed pseudogene ABCC6P1 resulted in a significant reduction of ABCC6 mRNA expression levels.The human genome contains a surprisingly small number of ABC transporter pseudogenes relative to other known gene families. They are unevenly distributed across the chromosomes. Importantly, a significant portion of the ABC transporter pseudogenes is transcriptionally active. The downregulation of ABCC6 mRNA levels by targeted suppression of the expression of its pseudogene ABCC6P1 provides evidence, for the first time, for a regulatory interdependence of a transcribed pseudogene and its protein coding counterpart in the human genome.
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Project description:A large number of pseudogenes have been found to be transcribed in human cancers. However, only a few pseudogenes are functionally characterized. Here, we identified a transcribed pseudogene of VEGFR1, or fms-related tyrosine kinase 1 (FLT1), in human colorectal cancer cells. Interestingly, this pseudogene (designated as FLT1P1) was found to be transcribed bidirectionally and functionally modulated cognate VEGFR1 protein expression in the cells. Mechanistically, expression of FLT1P1 antisense transcript not only inhibited the VEGFR1 expression, but also inhibited non-cognate VEGF-A expression through interaction with miR-520a. Perturbation of FLT1P1 expression by RNA interference (RNAi) markedly inhibited tumor cell proliferation and xenograft tumor growth. This study identifies FLT1P1 antisense as a critical regulator of VEGFR1 and VEGF-A expression in colorectal cancer cells, and highlights its role in regulation of the pathogenesis of colorectal cancer.The VEGFR1 pseudogene, FLT1P1, is a novel and functional regulator of VEGF signaling and its targeting could be an alternative strategy to modulate its cognate/target gene expression and downstream activity in cancer.
| S-EPMC4573265 | biostudies-literature