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Nature Communications Mar 2020Tumor cells often reprogram their metabolism for rapid proliferation. The roles of long noncoding RNAs (lncRNAs) in metabolism remodeling and the underlying mechanisms...
Tumor cells often reprogram their metabolism for rapid proliferation. The roles of long noncoding RNAs (lncRNAs) in metabolism remodeling and the underlying mechanisms remain elusive. Through screening, we found that the lncRNA Actin Gamma 1 Pseudogene (AGPG) is required for increased glycolysis activity and cell proliferation in esophageal squamous cell carcinoma (ESCC). Mechanistically, AGPG binds to and stabilizes 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). By preventing APC/C-mediated ubiquitination, AGPG protects PFKFB3 from proteasomal degradation, leading to the accumulation of PFKFB3 in cancer cells, which subsequently activates glycolytic flux and promotes cell cycle progression. AGPG is also a transcriptional target of p53; loss or mutation of TP53 triggers the marked upregulation of AGPG. Notably, inhibiting AGPG dramatically impaired tumor growth in patient-derived xenograft (PDX) models. Clinically, AGPG is highly expressed in many cancers, and high AGPG expression levels are correlated with poor prognosis, suggesting that AGPG is a potential biomarker and cancer therapeutic target.
Topics: Animals; Cell Line, Tumor; Cell Proliferation; Cellular Reprogramming; Esophageal Squamous Cell Carcinoma; Female; Gene Knockout Techniques; Glycolysis; Humans; Mice, Inbred BALB C; Mice, Nude; Phosphofructokinase-2; Pseudogenes; RNA, Long Noncoding; Up-Regulation; Xenograft Model Antitumor Assays
PubMed: 32198345
DOI: 10.1038/s41467-020-15112-3 -
Nature Methods Apr 2015HISAT (hierarchical indexing for spliced alignment of transcripts) is a highly efficient system for aligning reads from RNA sequencing experiments. HISAT uses an...
HISAT (hierarchical indexing for spliced alignment of transcripts) is a highly efficient system for aligning reads from RNA sequencing experiments. HISAT uses an indexing scheme based on the Burrows-Wheeler transform and the Ferragina-Manzini (FM) index, employing two types of indexes for alignment: a whole-genome FM index to anchor each alignment and numerous local FM indexes for very rapid extensions of these alignments. HISAT's hierarchical index for the human genome contains 48,000 local FM indexes, each representing a genomic region of ∼64,000 bp. Tests on real and simulated data sets showed that HISAT is the fastest system currently available, with equal or better accuracy than any other method. Despite its large number of indexes, HISAT requires only 4.3 gigabytes of memory. HISAT supports genomes of any size, including those larger than 4 billion bases.
Topics: Humans; Limit of Detection; Pseudogenes; Sequence Alignment; Sequence Analysis, DNA; Sequence Analysis, RNA
PubMed: 25751142
DOI: 10.1038/nmeth.3317 -
Nucleic Acids Research Jan 2023Ferroptosis is a mode of regulated cell death characterized by iron-dependent accumulation of lipid peroxidation. It is closely linked to the pathophysiological...
Ferroptosis is a mode of regulated cell death characterized by iron-dependent accumulation of lipid peroxidation. It is closely linked to the pathophysiological processes in many diseases. Since our publication of the first ferroptosis database in 2020 (FerrDb V1), many new findings have been published. To keep up with the rapid progress in ferroptosis research and to provide timely and high-quality data, here we present the successor, FerrDb V2. It contains 1001 ferroptosis regulators and 143 ferroptosis-disease associations manually curated from 3288 articles. Specifically, there are 621 gene regulators, of which 264 are drivers, 238 are suppressors, 9 are markers, and 110 are unclassified genes; and there are 380 substance regulators, with 201 inducers and 179 inhibitors. Compared to FerrDb V1, curated articles increase by >300%, ferroptosis regulators increase by 175%, and ferroptosis-disease associations increase by 50.5%. Circular RNA and pseudogene are novel regulators in FerrDb V2, and the percentage of non-coding RNA increases from 7.3% to 13.6%. External gene-related data were integrated, enabling thought-provoking and gene-oriented analysis in FerrDb V2. In conclusion, FerrDb V2 will help to acquire deeper insights into ferroptosis. FerrDb V2 is freely accessible at http://www.zhounan.org/ferrdb/.
Topics: Ferroptosis; Data Accuracy; Databases, Factual; Lipid Peroxidation; Pseudogenes
PubMed: 36305834
DOI: 10.1093/nar/gkac935 -
Proceedings of the National Academy of... Mar 2014Uricase is an enzyme involved in purine catabolism and is found in all three domains of life. Curiously, uricase is not functional in some organisms despite its role in...
Uricase is an enzyme involved in purine catabolism and is found in all three domains of life. Curiously, uricase is not functional in some organisms despite its role in converting highly insoluble uric acid into 5-hydroxyisourate. Of particular interest is the observation that apes, including humans, cannot oxidize uric acid, and it appears that multiple, independent evolutionary events led to the silencing or pseudogenization of the uricase gene in ancestral apes. Various arguments have been made to suggest why natural selection would allow the accumulation of uric acid despite the physiological consequences of crystallized monosodium urate acutely causing liver/kidney damage or chronically causing gout. We have applied evolutionary models to understand the history of primate uricases by resurrecting ancestral mammalian intermediates before the pseudogenization events of this gene family. Resurrected proteins reveal that ancestral uricases have steadily decreased in activity since the last common ancestor of mammals gave rise to descendent primate lineages. We were also able to determine the 3D distribution of amino acid replacements as they accumulated during evolutionary history by crystallizing a mammalian uricase protein. Further, ancient and modern uricases were stably transfected into HepG2 liver cells to test one hypothesis that uricase pseudogenization allowed ancient frugivorous apes to rapidly convert fructose into fat. Finally, pharmacokinetics of an ancient uricase injected in rodents suggest that our integrated approach provides the foundation for an evolutionarily-engineered enzyme capable of treating gout and preventing tumor lysis syndrome in human patients.
Topics: Adaptation, Biological; Adipose Tissue; Animals; Bayes Theorem; Computational Biology; DNA Primers; Evolution, Molecular; Fruit; Hep G2 Cells; Hominidae; Humans; Models, Biological; Models, Genetic; Models, Molecular; Phylogeny; Protein Conformation; Pseudogenes; Rats; Rats, Sprague-Dawley; Urate Oxidase
PubMed: 24550457
DOI: 10.1073/pnas.1320393111 -
FEBS Letters Feb 2000Pseudogenes are commonly encountered during investigation of the genomes of a wide range of life forms. This review concentrates on vertebrate, and in particular... (Review)
Review
Pseudogenes are commonly encountered during investigation of the genomes of a wide range of life forms. This review concentrates on vertebrate, and in particular mammalian, pseudogenes and describes their origin and subsequent evolution. Consideration is also given to pseudogenes that are transcribed and to the unusual group of genes that exist at the interface between functional genes and non-functional pseudogenes. As the sequences of different genomes are characterised, the recognition and interpretation of pseudogene sequences will become more important and have a greater impact in the field of molecular genetics.
Topics: Animals; Evolution, Molecular; Genome, Human; Humans; Pseudogenes; Retroelements; Vertebrates
PubMed: 10692568
DOI: 10.1016/s0014-5793(00)01199-6 -
Cell Research Jun 2016
Topics: Animals; High-Throughput Nucleotide Sequencing; Humans; Mice; Nucleic Acid Conformation; Primates; Pseudogenes; RNA; Rats; Retroelements; Sequence Analysis, RNA
PubMed: 27021280
DOI: 10.1038/cr.2016.42 -
Experimental Hematology Nov 2021Pseudogenes are DNA regions comprising defective copies of functional genes, the majority of which were generated by RNA- or DNA-level duplications. They exist across... (Review)
Review
Pseudogenes are DNA regions comprising defective copies of functional genes, the majority of which were generated by RNA- or DNA-level duplications. They exist across almost all forms of life and account for about one-quarter of the annotated genes in the human genome. Although these have been considered nonfunctional for decades, a growing number of pseudogenes have been found to be transcribed and to play crucial regulatory roles. Accumulating evidence indicates that they regulate gene expression through molecular interactions at the protein, RNA, and DNA levels. However, pseudogenes are often excluded in multiple genomewide analyses and functional screening, and their biological activities remain to be systematically disclosed. Here, we summarize the features of and progress of research on pseudogenes, in addition to discussing what is unknown about these genetic elements. Our previous findings, together with evidence of their poor conservation, prompted us to propose that pseudogenes may contribute to primate- or human-specific regulation, especially in hematopoiesis.
Topics: Animals; Gene Expression Regulation, Developmental; Gene Expression Regulation, Leukemic; Hematopoiesis; Humans; Leukemia; Pseudogenes
PubMed: 34517065
DOI: 10.1016/j.exphem.2021.09.001 -
Journal of Cellular and Molecular... Jan 2017The concept of competitive endogenous RNA (ceRNA) was first proposed by Salmena and colleagues. Evidence suggests that pseudogene RNAs can act as a 'sponge' through... (Review)
Review
The concept of competitive endogenous RNA (ceRNA) was first proposed by Salmena and colleagues. Evidence suggests that pseudogene RNAs can act as a 'sponge' through competitive binding of common miRNA, releasing or attenuating repression through sequestering miRNAs away from parental mRNA. In theory, ceRNAs refer to all transcripts such as mRNA, tRNA, rRNA, long non-coding RNA, pseudogene RNA and circular RNA, because all of them may become the targets of miRNA depending on spatiotemporal situation. As binding of miRNA to the target RNA is not 100% complementary, it is possible that one miRNA can bind to multiple target RNAs and vice versa. All RNAs crosstalk through competitively binding to miRNAvia miRNA response elements (MREs) contained within the RNA sequences, thus forming a complex regulatory network. The ratio of a subset of miRNAs to the corresponding number of MREs determines repression strength on a given mRNA translation or stability. An increase in pseudogene RNA level can sequester miRNA and release repression on the parental gene, leading to an increase in parental gene expression. A massive number of transcripts constitute a complicated network that regulates each other through this proposed mechanism, though some regulatory significance may be mild or even undetectable. It is possible that the regulation of gene and pseudogene expression occurring in this manor involves all RNAs bearing common MREs. In this review, we will primarily discuss how pseudogene transcripts regulate expression of parental genes via ceRNA network and biological significance of regulation.
Topics: Animals; Gene Expression; Gene Regulatory Networks; Humans; Pseudogenes; RNA; Response Elements
PubMed: 27561207
DOI: 10.1111/jcmm.12952 -
Current Opinion in Microbiology Feb 2015Pseudogenes are defined as fragments of once-functional genes that have been silenced by one or more nonsense, frameshift or missense mutations. Despite continuing... (Review)
Review
Pseudogenes are defined as fragments of once-functional genes that have been silenced by one or more nonsense, frameshift or missense mutations. Despite continuing increases in the speed of sequencing and annotating bacterial genomes, the identification and categorisation of pseudogenes remains problematic. Even when identified, pseudogenes are considered to be rare and tend to be ignored. On the contrary, pseudogenes are surprisingly prevalent and can persist for long evolutionary time periods, representing a record of once-functional genetic characteristics. Most importantly, pseudogenes provide an insight into prokaryotic evolutionary history as a record of phenotypic traits that have been lost. Focusing on the intracellular and symbiotic bacteria in which pseudogenes predominate, this review discusses the importance of identifying pseudogenes to fully understand the abilities of bacteria, and to understand prokaryotes within their evolutionary context.
Topics: Bacteria; Evolution, Molecular; Pseudogenes
PubMed: 25461580
DOI: 10.1016/j.mib.2014.11.012 -
The Plant Journal : For Cell and... Feb 2018Pseudogenes have a reputation of being 'evolutionary relics' or 'junk DNA'. While they are well characterized in mammals, studies in more complex plant genomes have so...
Pseudogenes have a reputation of being 'evolutionary relics' or 'junk DNA'. While they are well characterized in mammals, studies in more complex plant genomes have so far been hampered by the absence of reference genome sequences. Barley is one of the economically most important cereals and has a genome size of 5.1 Gb. With the first high-quality genome reference assembly available for a Triticeae crop, we conducted a whole-genome assessment of pseudogenes on the barley genome. We identified, characterized and classified 89 440 gene fragments and pseudogenes scattered along the chromosomes, with occasional hotspots and higher densities at the chromosome ends. Full-length pseudogenes (11 015) have preferentially retained their exon-intron structure. Retrotransposition of processed mRNAs only plays a marginal role in their creation. However, the distribution of retroposed pseudogenes reflects the Rabl configuration of barley chromosomes and thus hints at founding mechanisms. While parent genes related to the defense-response were found to be under-represented in cultivated barley, we detected several defense-related pseudogenes in wild barley accessions. The percentage of transcriptionally active pseudogenes is 7.2%, and these may potentially adopt new regulatory roles.The barley genome is rich in pseudogenes and small gene fragments mainly located towards chromosome tips or as tandemly repeated units. Our results indicate non-random duplication and pseudogenization preferences and improve our understanding of the dynamics of gene birth and death in large plant genomes and the mechanisms that lead to evolutionary innovations.
Topics: Chromosome Mapping; Chromosomes, Plant; Gene Duplication; Genes, Plant; Hordeum; Multigene Family; Pseudogenes; Selection, Genetic; Synteny
PubMed: 29205595
DOI: 10.1111/tpj.13794