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A FTH1 gene:pseudogene:miRNA network regulates tumorigenesis in prostate cancer

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE101837 | GEO | 2017/07/26

SECONDARY ACCESSION(S): PRJNA395659

REPOSITORIES: GEO

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Project description:Approximately half of M. lepraeâ??s transcriptome consists of inactive gene products. This has an impact on overall energy and resource consumption without potential benefit to this organism. However, multiple translational â??silencingâ?? mechanisms are present, reducing additional energy and resource expenditure required for protein production from these transcripts. The Mycobacterium leprae genome has less than 50% coding capacity and 1,133 pseudogenes. Preliminary evidence suggests that some pseudogenes are expressed. Therefore, defining pseudogene transcriptional and translational potentials should increase our understanding of their impact on M. leprae physiology. To address this, M. leprae was purified from the granulomatous hind footpad tissue of four individual nu/nu nude mice six months post-infection. M. leprae whole genome DNA microarrays representing the 1,614 annotated ORFs and 1,133 identified pseudogenes, were obtained from the Leprosy Research Support and Maintenance of an Armadillo Colony Post-Genome Era, Part I: Leprosy Research Support Contract (NO1 AI-25469) at Colorado State University. To validate 20% of genes positive by microarray analysis, RT-PCR was performed. Results of this study Gene expression analysis identified transcripts from 49% of all M. leprae genes including 57% of all ORFs and 43% of all pseudogenes in the genome. Pseudogenes were randomly distributed throughout the chromosome. Factors resulting in pseudogene transcription included: 1) co-orientation of transcribed pseudogenes with transcribed ORFs within or exclusive of operon-like structures; 2) the paucity of intrinsic stem-loop transcriptional terminators between transcribed ORFs and downstream pseudogenes; and 3) predicted pseudogene promoters. Mechanisms for translational silencing of pseudogene transcripts included the lack of both translational start codons and strong Shine-Dalgarno sequences. Transcribed pseudogenes also contained multiple in-frame stop codons and high Ka/Ks ratios, compared to that of homologs in M. tuberculosis and ORFs in M. leprae. A pseudogene transcript containing an active promoter, strong SD site, a start codon, but containing two in frame stop codons yielded a protein product when expressed in E. coli. Approximately half of M. leprae's transcriptome consists of inactive gene products consuming energy and resources without potential benefit to M. leprae. Presently it is unclear what additional detrimental affect(s) this large number of inactive mRNAs has on the functional capability of this organism. Translation of these pseudogenes may play an important role in overall energy consumption and resultant pathophysiological characteristics of M. leprae. However, this study also demonstrated that multiple translational silencing mechanisms are present, reducing additional energy and resource expenditure required for protein production from the vast majority of these transcripts. The overall design of this study was to identify the transcriptome of M. leprae in the granulomatous tissue of the mouse hind foot pad 6 months post infection.

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A FTH1 gene:pseudogene:miRNA network regulates tumorigenesis in prostate cancer

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