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Methods in Molecular Biology (Clifton,... 2021Aberrant expression of pseudogenes has been observed in many cancer types. Deregulated pseudogenes engage in a multitude of biological processes at the DNA, RNA, and... (Review)
Review
Aberrant expression of pseudogenes has been observed in many cancer types. Deregulated pseudogenes engage in a multitude of biological processes at the DNA, RNA, and protein levels and eventually facilitate disease progression. To investigate pseudogene functions in cancer, cell lines and cell line transplantation models have been widely used. However, cancer biology is best studied in the context of an intact organism. Here, we present various strategies to investigate pseudogenes in genetically engineered mouse models and discuss advantages and disadvantages of the different approaches.
Topics: Animals; Cell Line, Tumor; Drug Resistance, Microbial; Embryonic Stem Cells; Gene Expression Regulation; Genes, Synthetic; Heterografts; Humans; Mice; Mice, Transgenic; Molecular Targeted Therapy; Neoplasm Transplantation; Neoplasms, Experimental; Promoter Regions, Genetic; Pseudogenes; RNA Interference; Recombinant Proteins; Species Specificity; Tetracycline; Up-Regulation
PubMed: 34165722
DOI: 10.1007/978-1-0716-1503-4_18 -
Journal of Immunology (Baltimore, Md. :... Jan 2022The biological relevance of genes initially categorized as "pseudogenes" is slowly emerging, notably in innate immunity. In the HLA region on chromosome 6, is one such...
The biological relevance of genes initially categorized as "pseudogenes" is slowly emerging, notably in innate immunity. In the HLA region on chromosome 6, is one such pseudogene; yet, it is transcribed, and its variation is associated with immune properties. Furthermore, two alleles, * and *, putatively encode a complete, membrane-bound HLA protein. Here we thus hypothesized that HLA-H contributes to immune homeostasis similarly to tolerogenic molecules HLA-G, -E, and -F. We tested if * encodes a membrane-bound protein that can inhibit the cytotoxicity of effector cells. We used an HLA-null human erythroblast cell line transduced with * cDNA to demonstrate that HLA-H*02:07 encodes a membrane-bound protein. Additionally, using a cytotoxicity assay, our results support that K562 * inhibits human effector IL-2-activated PBMCs and human IL-2-independent NK92-MI cell line activity. Finally, through in silico genotyping of the Denisovan genome and haplotypic association with Denisovan-derived *, we also show that * is of archaic origin. Hence, admixture with archaic humans brought a functional allele into modern European and Asian populations.
Topics: Alleles; Asian People; Cell Membrane; Cytotoxicity, Immunologic; Evolution, Molecular; Gene Frequency; Genotype; HLA-A11 Antigen; Haplotypes; Hemochromatosis Protein; Homeostasis; Humans; Immune Tolerance; K562 Cells; Killer Cells, Natural; Lymphocyte Activation; Pseudogenes; White People
PubMed: 34872977
DOI: 10.4049/jimmunol.2100358 -
Nucleic Acids Research Jul 2023Several atlasing efforts aim to profile human gene and protein expression across tissues, cell types and cell lines in normal physiology, development and disease. One...
Several atlasing efforts aim to profile human gene and protein expression across tissues, cell types and cell lines in normal physiology, development and disease. One utility of these resources is to examine the expression of a single gene across all cell types, tissues and cell lines in each atlas. However, there is currently no centralized place that integrates data from several atlases to provide this type of data in a uniform format for visualization, analysis and download, and via an application programming interface. To address this need, GeneRanger is a web server that provides access to processed data about gene and protein expression across normal human cell types, tissues and cell lines from several atlases. At the same time, TargetRanger is a related web server that takes as input RNA-seq data from profiled human cells and tissues, and then compares the uploaded input data to expression levels across the atlases to identify genes that are highly expressed in the input and lowly expressed across normal human cell types and tissues. Identified targets can be filtered by transmembrane or secreted proteins. The results from GeneRanger and TargetRanger are visualized as box and scatter plots, and as interactive tables. GeneRanger and TargetRanger are available from https://generanger.maayanlab.cloud and https://targetranger.maayanlab.cloud, respectively.
Topics: Humans; Cell Line; Proteomics; Pseudogenes; RNA-Seq; Software; Internet
PubMed: 37166966
DOI: 10.1093/nar/gkad399 -
Scientific Reports Oct 2022Colorectal cancer (CRC) is one of the most common and malignant carcinomas. Many long noncoding RNAs (lncRNAs) have been reported to play important roles in the...
Colorectal cancer (CRC) is one of the most common and malignant carcinomas. Many long noncoding RNAs (lncRNAs) have been reported to play important roles in the tumorigenesis of CRC by influencing the expression of some mRNAs via competing endogenous RNA (ceRNA) networks and interacting with miRNAs. Pseudogene is one kind of lncRNA and can act as RNA sponges for miRNAs and regulate gene expression via ceRNA networks. However, there are few studies about pseudogenes in CRC. In this study, 31 differentially expressed (DE) pseudogenes, 17 DE miRNAs and 152 DE mRNAs were identified by analyzing the expression profiles of colon adenocarcinoma obtained from The Cancer Genome Atlas. A ceRNA network was constructed based on these RNAs. Kaplan-Meier analysis showed that 7 pseudogenes, 4 miRNAs and 30 mRNAs were significantly associated with overall survival. Then multivariate Cox regression analysis of the ceRNA-related DE pseudogenes was performed and a 5-pseudogene signature with the greatest prognostic value for CRC was identified. Moreover, the results were validated by the Gene Expression Omnibus database, and quantitative real-time PCR in 113 pairs of CRC tissues and colon cancer cell lines. This study provides a pseudogene-associated ceRNA network, 7 prognostic pseudogene biomarkers, and a 5-pseudogene prognostic risk signature that may be useful for predicting the survival of CRC patients.
Topics: Humans; RNA, Long Noncoding; Prognosis; Pseudogenes; Gene Regulatory Networks; Gene Expression Regulation, Neoplastic; Adenocarcinoma; Colonic Neoplasms; MicroRNAs; RNA, Messenger; Biomarkers
PubMed: 36272991
DOI: 10.1038/s41598-022-22768-y -
Genome Biology Jan 2021PIWI proteins, a subfamily of PAZ/PIWI Domain family RNA-binding proteins, are best known for their function in silencing transposons and germline development by... (Review)
Review
PIWI proteins, a subfamily of PAZ/PIWI Domain family RNA-binding proteins, are best known for their function in silencing transposons and germline development by partnering with small noncoding RNAs called PIWI-interacting RNAs (piRNAs). However, recent studies have revealed multifaceted roles of the PIWI-piRNA pathway in regulating the expression of other major classes of RNAs in germ cells. In this review, we summarize how PIWI proteins and piRNAs regulate the expression of many disparate RNAs, describing a highly complex global genomic regulatory relationship at the RNA level through which piRNAs functionally connect all major constituents of the genome in the germline.
Topics: Animals; Caenorhabditis elegans; DNA Transposable Elements; Drosophila; Drosophila Proteins; Gene Expression Regulation, Developmental; Gene Silencing; Germ Cells; Pseudogenes; RNA, Long Noncoding; RNA, Messenger; RNA, Small Interfering; RNA-Binding Proteins
PubMed: 33419460
DOI: 10.1186/s13059-020-02221-x -
Frontiers in Genetics 2021Pseudogenes were originally regarded as non-functional components scattered in the genome during evolution. Recent studies have shown that pseudogenes can be transcribed... (Review)
Review
Pseudogenes were originally regarded as non-functional components scattered in the genome during evolution. Recent studies have shown that pseudogenes can be transcribed into long non-coding RNA and play a key role at multiple functional levels in different physiological and pathological processes. microRNAs (miRNAs) are a type of non-coding RNA, which plays important regulatory roles in cells. Numerous studies have shown that pseudogenes and miRNAs have interactions and form a ceRNA network with mRNA to regulate biological processes and involve diseases. Exploring the associations of pseudogenes and miRNAs will facilitate the clinical diagnosis of some diseases. Here, we propose a prediction model PMGAE (Pseudogene-MiRNA association prediction based on the Graph Auto-Encoder), which incorporates feature fusion, graph auto-encoder (GAE), and eXtreme Gradient Boosting (XGBoost). First, we calculated three types of similarities including Jaccard similarity, cosine similarity, and Pearson similarity between nodes based on the biological characteristics of pseudogenes and miRNAs. Subsequently, we fused the above similarities to construct a similarity profile as the initial representation features for nodes. Then, we aggregated the similarity profiles and associations of nodes to obtain the low-dimensional representation vector of nodes through a GAE. In the last step, we fed these representation vectors into an XGBoost classifier to predict new pseudogene-miRNA associations (PMAs). The results of five-fold cross validation show that PMGAE achieves a mean AUC of 0.8634 and mean AUPR of 0.8966. Case studies further substantiated the reliability of PMGAE for mining PMAs and the study of endogenous RNA networks in relation to diseases.
PubMed: 34966413
DOI: 10.3389/fgene.2021.781277 -
Hepatology (Baltimore, Md.) Jun 2023Interferon (IFN) signaling is critical to the pathogenesis of alcohol-associated hepatitis (AH), yet the mechanisms for activation of this system are elusive. We...
BACKGROUND AND AIMS
Interferon (IFN) signaling is critical to the pathogenesis of alcohol-associated hepatitis (AH), yet the mechanisms for activation of this system are elusive. We hypothesize that host-derived 5S rRNA pseudogene (RNA5SP) transcripts regulate IFN production and modify immunity in AH.
APPROACH AND RESULTS
Mining of transcriptomic datasets revealed that in patients with severe alcohol-associated hepatitis (sAH), hepatic expression of genes regulated by IFNs was perturbed and gene sets involved in IFN production were enriched. RNA5SP transcripts were also increased and correlated with expression of type I IFNs. Interestingly, inflammatory mediators upregulated in sAH, but not in other liver diseases, were positively correlated with certain RNA5SP transcripts. Real-time quantitative PCR demonstrated that RNA5SP transcripts were upregulated in peripheral blood mononuclear cells (PBMCs) from patients with sAH. In sAH livers, increased 5S rRNA and reduced nuclear MAF1 (MAF1 homolog, negative regulator of RNA polymerase III) protein suggested a higher activity of RNA polymerase III (Pol III); inhibition of Pol III reduced RNA5SP expression in monocytic THP-1 cells. Expression of several RNA5SP transcript-interacting proteins was downregulated in sAH, potentially unmasking transcripts to immunosensors. Indeed, siRNA knockdown of interacting proteins potentiated the immunostimulatory activity of RNA5SP transcripts. Molecular interaction and cell viability assays demonstrated that RNA5SP transcripts adopted Z-conformation and contributed to ZBP1-mediated caspase-independent cell death.
CONCLUSIONS
Increased expression and binding availability of RNA5SP transcripts was associated with hepatic IFN production and inflammation in sAH. These data identify RNA5SP transcripts as a potential target to mitigate inflammation and hepatocellular injury in AH.
Topics: Humans; RNA, Ribosomal, 5S; Pseudogenes; RNA Polymerase III; Biosensing Techniques; Leukocytes, Mononuclear; Immunoassay; Inflammation; Hepatitis, Alcoholic; Interferon Type I
PubMed: 36645226
DOI: 10.1097/HEP.0000000000000024 -
Methods in Molecular Biology (Clifton,... 2021Long intergenic noncoding RNAs (lincRNAs) are known to be tissue specifically expressed and able to regulate functional protein-coding genes: some can even act as...
Long intergenic noncoding RNAs (lincRNAs) are known to be tissue specifically expressed and able to regulate functional protein-coding genes: some can even act as competing endogenous RNAs (ceRNAs), because microRNAs can bind to them instead of the corresponding mRNA binding sites. Some lincRNAs contain remnants of protein-coding sequences and it has been hypothesized that they might arise after a pseudogenization processes. However, a major limitation in the study of such phenomenon is the lack of proper computational tools designed to align/analyze protein-coding sequences and noncoding sequences. To overcome this limitation, we published a method that finds the remnants of protein-coding sequences within the sequence of lincRNAs, as well as the corresponding sequences in parental proteins. This method, together with the visualization platform for tracing frameshifts and single point mutations within this type of sequences, are described here.
Topics: Amino Acid Sequence; Computational Biology; MicroRNAs; Open Reading Frames; Pseudogenes; RNA, Long Noncoding; RNA, Messenger; Sequence Alignment; Sequence Analysis, RNA
PubMed: 34165708
DOI: 10.1007/978-1-0716-1503-4_4 -
Bioinformatics and Biology Insights 2021Pseudogenes have been classified as functionless and their annotation is an ongoing problem. The Adh6-ps1-a mouse pseudogene belonging to the alcohol dehydrogenase gene...
Pseudogenes have been classified as functionless and their annotation is an ongoing problem. The Adh6-ps1-a mouse pseudogene belonging to the alcohol dehydrogenase gene complex (Adh) was analyzed to review the conservation, homology, expression, and interactions and identify any role it plays in disease phenotypes using bioinformatics databases. Results showed that Adh6-ps1 have 2 transcripts (processed and unprocessed) which may have emerged from a transposition and duplication event, respectively, and that induced inversions (Uox gene, In(3)11Rk) involving gene complexes associated with Adh6-ps1 have been implicated in a diverse range of diseases. Adh6-ps1 is highly conserved in vertebrates particularly rodents and expressed in the liver. The top 5 MirRNA targets were Mir455, Mir511, Mir1903, Mir361, and Mir669o markers. While much is unknown about Mir1903 and Mir669o, the silencing of Mir455 and Mir511 is linked with hepatocellular carcinoma (HCC), and Mir361 is implicated in endometrial cancers. Given the identified MirRNA interactions with Adh6-ps1 and its expression in HCC and reproductive systems, it may well have a role in tumorigenesis and disease phenotypes. Nonetheless, further studies are required to establish these facts to add to the growing efforts to understand pseudogenes and their potential involvement in disease conditions.
PubMed: 34413637
DOI: 10.1177/11779322211040591 -
Nature Genetics Aug 2020Standardized gene naming is crucial for effective communication about genes, and as genomics becomes increasingly important in healthcare, the need for a consistent...
Standardized gene naming is crucial for effective communication about genes, and as genomics becomes increasingly important in healthcare, the need for a consistent language for human genes becomes ever more vital. Here we present the current HUGO Gene Nomenclature Committee (HGNC) guidelines for naming not only protein-coding but also RNA genes and pseudogenes, and outline the changes in approach and ethos that have resulted from the discoveries of the last few decades.
Topics: Genes; Human Genetics; Humans; Pseudogenes; RNA
PubMed: 32747822
DOI: 10.1038/s41588-020-0669-3