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Genome Biology Nov 2022Pseudogenes are excellent markers for genome evolution, which are emerging as crucial regulators of development and disease, especially cancer. However, systematic...
BACKGROUND
Pseudogenes are excellent markers for genome evolution, which are emerging as crucial regulators of development and disease, especially cancer. However, systematic functional characterization and evolution of pseudogenes remain largely unexplored.
RESULTS
To systematically characterize pseudogenes, we date the origin of human and mouse pseudogenes across vertebrates and observe a burst of pseudogene gain in these two lineages. Based on a hybrid sequencing dataset combining full-length PacBio sequencing, sample-matched Illumina sequencing, and public time-course transcriptome data, we observe that abundant mammalian pseudogenes could be transcribed, which contribute to the establishment of organ identity. Our analyses reveal that developmentally dynamic pseudogenes are evolutionarily conserved and show an increasing weight during development. Besides, they are involved in complex transcriptional and post-transcriptional modulation, exhibiting the signatures of functional enrichment. Coding potential evaluation suggests that 19% of human pseudogenes could be translated, thus serving as a new way for protein innovation. Moreover, pseudogenes carry disease-associated SNPs and conduce to cancer transcriptome perturbation.
CONCLUSIONS
Our discovery reveals an unexpectedly high abundance of mammalian pseudogenes that can be transcribed and translated, and these pseudogenes represent a novel regulatory layer. Our study also prioritizes developmentally dynamic pseudogenes with signatures of functional enrichment and provides a hybrid sequencing dataset for further unraveling their biological mechanisms in organ development and carcinogenesis in the future.
Topics: Humans; Mice; Animals; Pseudogenes; Genome; Mammals; Sequence Analysis, DNA; Neoplasms
PubMed: 36348461
DOI: 10.1186/s13059-022-02802-y -
Methods in Molecular Biology (Clifton,... 2022Analysis of the proteome, combined with the human genome sequence, improved gene annotation and confirmed that some genes are actually expressed as proteins, including...
Analysis of the proteome, combined with the human genome sequence, improved gene annotation and confirmed that some genes are actually expressed as proteins, including pseudogenes, alternative reading frames, and additional protein isoforms. Although sequencing a genome is a challenge in itself, the annotation of all genes encoding proteins is a bigger one. Here, we describe an in silico approach to identify evidence of pseudogene expression, as well as an experimental approach for the validation of the protein encoded by pseudogenes, including the steps necessary to quantify these proteins. This technique enables a comprehensive analysis for the expression of genes into proteins that were not suspected of existing.
Topics: Genome, Human; Humans; Molecular Sequence Annotation; Proteome; Proteomics; Pseudogenes
PubMed: 35612746
DOI: 10.1007/978-1-0716-2124-0_16 -
Methods in Molecular Biology (Clifton,... 2021Transcription termination is a critical stage for the production of legitimate mRNAs, and consequently functional proteins. However, the transcription machinery can...
Transcription termination is a critical stage for the production of legitimate mRNAs, and consequently functional proteins. However, the transcription machinery can ignore the stop signs and continue elongating beyond gene boundaries, invading downstream neighboring genes. Such phenomenon, designated transcription readthrough, can trigger the expression of pseudogenes usually silenced or lacking the proper regulatory signals. Due to the sequence similarity to parental genes, readthrough transcribed pseudogenes can regulate relevant protein-coding genes and impact biological functions. Here, we describe a computational pipeline that employs already existent bioinformatic tools to detect readthrough transcribed pseudogenes from expression profiles. We also unveil that combining strand-specific transcriptome data and epigenetic profiles can enhance and corroborate the results. By applying such approach to renal cancer biopsies, we show that pseudogenes can be readthrough transcribed as part of unspliced transcripts or processed RNA chimeras. Overall, our pipeline allows us to scrutinize transcriptome profiles to detect a diversity of readthrough events leading to expression of pseudogenes.
Topics: Computational Biology; Databases, Genetic; Epigenomics; Gene Expression Profiling; Gene Expression Regulation; Humans; Kidney Neoplasms; Mutant Chimeric Proteins; Peptide Chain Termination, Translational; Pseudogenes; RNA, Messenger; RNA-Seq; Software; Transcription, Genetic; Transcriptome
PubMed: 34165710
DOI: 10.1007/978-1-0716-1503-4_6 -
Experimental Cell Research Sep 2022Preeclampsia (PE) is a pregnancy-associated complication accompanied by gestational hypertension and proteinuria, affecting 2-8% of pregnancies globally. The placental...
Preeclampsia (PE) is a pregnancy-associated complication accompanied by gestational hypertension and proteinuria, affecting 2-8% of pregnancies globally. The placental trophoblast cell invasion of decidua and myometrium during early gestation is crucial for healthy placentation. Thus, trophoblast dysfunction might contribute to PE onset. Therefore, further investigations are needed to elucidate the underlying mechanism of trophoblast cell functions. In the present study, we identified a novel pseudogene named C-Type Lectin Domain Family 4 Member G Pseudogene 1 (CLEC4GP1), which was aberrantly expressed in PE placental tissues. In vitro analyses showed that CLEC4GP1 overexpression significantly increased the cell viability and invasiveness and decreased the apoptosis rate of HTR-8/SVneo and JEG-3 cells, while CLEC4GP1 knockdown exerted opposite effects, suggesting the beneficial role of CLEC4GP1 in trophoblast cells. Next, co-expression analysis found that CLEC4GP1 was negatively correlated with Interleukin 15 (IL-15). The expression of IL-15 dramatically increased in PE placental tissues. In HTR-8/SVneo and JEG-3 cells, IL-15 exhibited detrimental effects, opposite to CLEC4GP1, and they were negatively correlated. In addition, CLEC4GP1 attenuates the mRNA stability of IL-16 by inhibiting the binding between human antigen R (HuR) protein and IL-15 RNA. Finally, the obverse effects of CLEC4GP1 and IL-15 were investigated, and results showed that IL-15 reverted CLEC4GP1 induced cellular functions. In brief, these data suggest that CLEC4GP1/IL-15 axis might modulate the occurrence and progression of PE via influencing the trophoblast cell viability, apoptosis, and invasive capability. This study provided cognizance of targeting the CLEC4GP1/IL-15 axis as a novel therapeutic approach to mitigate PE progression.
Topics: Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Humans; Interleukin-15; Placenta; Pre-Eclampsia; Pregnancy; Pseudogenes; Trophoblasts
PubMed: 35605650
DOI: 10.1016/j.yexcr.2022.113215 -
Briefings in Functional Genomics Nov 2017Cancer burden rises globally at an alarming pace. According to GLOBOCAN 2012, gastric cancer (GC) is regarded as the fifth most common malignancy in the world. Being... (Review)
Review
Cancer burden rises globally at an alarming pace. According to GLOBOCAN 2012, gastric cancer (GC) is regarded as the fifth most common malignancy in the world. Being twice as high in men as in women, GC is the third leading cause of cancer mortality in both sexes globally. Being labeled as 'junk DNA', pseudogenes were considered as nonfunctional 'trash', which contribute nothing to survival of the organism; therefore, a number of strategies have been developed to circumvent their accidental detection. Recent progresses have confirmed that pseudogenes can have broad and multifaceted spectrum of activities in human cancers in general and GC in particular. Furthermore, the mentioned functions are parental gene-dependent and/or -independent. Therefore, pseudogenes can be regarded as the emerging class of elaborate modulators of gene expression involved in pathogenesis of human cancers including gastric adenocarcinoma.
Topics: Female; Humans; Male; Pseudogenes; Stomach Neoplasms
PubMed: 28459995
DOI: 10.1093/bfgp/elx004 -
Molecular Biology and Evolution Jun 2020Mobile genetic elements (MGEs) often encode integrases which catalyze the site-specific insertion of their genetic information into the host genome and the reverse...
Mobile genetic elements (MGEs) often encode integrases which catalyze the site-specific insertion of their genetic information into the host genome and the reverse reaction of excision. Hyperthermophilic archaea harbor integrases belonging to the SSV-family which carry the MGE recombination site within their open reading frame. Upon integration into the host genome, SSV integrases disrupt their own gene into two inactive pseudogenes and are termed suicidal for this reason. The evolutionary maintenance of suicidal integrases, concurring with the high prevalence and multiples recruitments of these recombinases by archaeal MGEs, is highly paradoxical. To elucidate this phenomenon, we analyzed the wide phylogenomic distribution of a prominent class of suicidal integrases which revealed a highly variable integration site specificity. Our results highlighted the remarkable hybrid nature of these enzymes encoded from the assembly of inactive pseudogenes of different origins. The characterization of the biological properties of one of these integrases, IntpT26-2 showed that this enzyme was active over a wide range of temperatures up to 99 °C and displayed a less-stringent site specificity requirement than comparable integrases. These observations concurred in explaining the pervasiveness of these suicidal integrases in the most hyperthermophilic organisms. The biochemical and phylogenomic data presented here revealed a target site switching system operating on highly thermostable integrases and suggested a new model for split gene reconstitution. By generating fast-evolving pseudogenes at high frequency, suicidal integrases constitute a powerful model to approach the molecular mechanisms involved in the generation of active genes variants by the recombination of proto-genes.
Topics: Evolution, Molecular; Hydrothermal Vents; Integrases; Interspersed Repetitive Sequences; Pseudogenes; Thermococcus
PubMed: 32068866
DOI: 10.1093/molbev/msaa041 -
Plant Signaling & Behavior 2019Pseudogenes, nonfunctional genomic sequences derived from functional protein-coding genes, form by duplication or retrotransposition, and loss of gene function by...
Pseudogenes, nonfunctional genomic sequences derived from functional protein-coding genes, form by duplication or retrotransposition, and loss of gene function by disabling mutations. Studies on the evolution and functional aspects of plant pseudogenes are limited, despite their abundance in the plant genome. To date, most researches on pseudogenes focus on mammals. Here, we summarized current knowledge on pseudogenes including the historical and recent progress, analyzes their essential roles in gene regulation in hope of further stimulating researches in plant species for understanding gene regulation and evolution.
Topics: Animals; Evolution, Molecular; Gene Expression Regulation; Genome, Plant; Humans; Mutation; Pseudogenes
PubMed: 31161861
DOI: 10.1080/15592324.2019.1625698 -
The International Journal of... Sep 2014A paradigm shift is sweeping modern day molecular biology following the realisation that large amounts of "junk" DNA", thought initially to be evolutionary remnants, may... (Review)
Review
A paradigm shift is sweeping modern day molecular biology following the realisation that large amounts of "junk" DNA", thought initially to be evolutionary remnants, may actually be functional. Several recent studies support a functional role for pseudogene-expressed non-coding RNAs in regulating their protein-coding counterparts. Several hundreds of pseudogenes have been reported as transcribed into RNA in a large variety of tissues and tumours. Most studies have focused on pseudogenes expressed in the sense direction, but some reports suggest that pseudogenes can also be transcribed as antisense RNAs (asRNAs). A few examples of key regulatory genes, such as PTEN and OCT4, have in fact been reported to be under the regulation of pseudogene-expressed asRNAs. Here, we review what are known about pseudogene expressed non-coding RNA mediated gene regulation and their roles in the control of epigenetic states. This article is part of a Directed Issue entitled: The Non-coding RNA Revolution.
Topics: Animals; Epigenomics; Gene Expression Regulation; Humans; Pseudogenes; RNA, Antisense; RNA, Long Noncoding; Transcription, Genetic
PubMed: 24842102
DOI: 10.1016/j.biocel.2014.05.008 -
Nature Communications Mar 2020Pseudogenes are mutated copies of protein-coding genes that cannot be translated into proteins, but a small subset of pseudogenes has been detected at the protein level....
Pseudogenes are mutated copies of protein-coding genes that cannot be translated into proteins, but a small subset of pseudogenes has been detected at the protein level. Although ubiquitin pseudogenes represent one of the most abundant pseudogene families in many organisms, little is known about their expression and signaling potential. By re-analyzing public RNA-sequencing and proteomics datasets, we here provide evidence for the expression of several ubiquitin pseudogenes including UBB pseudogene 4 (UBBP4), which encodes Ub (Q2K, K33E, Q49K, N60S). The functional consequences of Ub conjugation appear to differ from canonical ubiquitylation. Quantitative proteomics shows that Ub modifies specific proteins including lamins. Knockout of UBBP4 results in slower cell division, and accumulation of lamin A within the nucleolus. Our work suggests that a subset of proteins reported as ubiquitin targets may instead be modified by ubiquitin variants that are the products of wrongly annotated pseudogenes and induce different functional effects.
Topics: CRISPR-Cas Systems; Cell Division; Cell Nucleus; Cloning, Molecular; Datasets as Topic; Gene Knockout Techniques; HEK293 Cells; HeLa Cells; Humans; Lamin Type A; Proteomics; Pseudogenes; RNA-Seq; Ubiquitin; Ubiquitination
PubMed: 32161257
DOI: 10.1038/s41467-020-15090-6 -
Pacific Symposium on Biocomputing.... 2018Pseudogenes are fossil relatives of genes. Pseudogenes have long been thought of as "junk DNAs", since they do not code proteins in normal tissues. Although most of the...
Pseudogenes are fossil relatives of genes. Pseudogenes have long been thought of as "junk DNAs", since they do not code proteins in normal tissues. Although most of the human pseudogenes do not have noticeable functions, ∼20% of them exhibit transcriptional activity. There has been evidence showing that some pseudogenes adopted functions as lncRNAs and work as regulators of gene expression. Furthermore, pseudogenes can even be "reactivated" in some conditions, such as cancer initiation. Some pseudogenes are transcribed in specific cancer types, and some are even translated into proteins as observed in several cancer cell lines. All the above have shown that pseudogenes could have functional roles or potentials in the genome. Evaluating the relationships between pseudogenes and their gene counterparts could help us reveal the evolutionary path of pseudogenes and associate pseudogenes with functional potentials. It also provides an insight into the regulatory networks involving pseudogenes with transcriptional and even translational activities.In this study, we develop a novel approach integrating graph analysis, sequence alignment and functional analysis to evaluate pseudogene-gene relationships, and apply it to human gene homologs and pseudogenes. We generated a comprehensive set of 445 pseudogene-gene (PGG) families from the original 3,281 gene families (13.56%). Of these 438 (98.4% PGG, 13.3% total) were non-trivial (containing more than one pseudogene). Each PGG family contains multiple genes and pseudogenes with high sequence similarity. For each family, we generate a sequence alignment network and phylogenetic trees recapitulating the evolutionary paths. We find evidence supporting the evolution history of olfactory family (both genes and pseudogenes) in human, which also supports the validity of our analysis method. Next, we evaluate these networks in respect to the gene ontology from which we identify functions enriched in these pseudogene-gene families and infer functional impact of pseudogenes involved in the networks. This demonstrates the application of our PGG network database in the study of pseudogene function in disease context.
Topics: Chromosome Mapping; Computational Biology; Conserved Sequence; DNA, Intergenic; Databases, Genetic; Evolution, Molecular; Gene Ontology; Gene Regulatory Networks; Humans; Markov Chains; Models, Genetic; Multigene Family; Phylogeny; Pseudogenes; Sequence Alignment; Smell
PubMed: 29218912
DOI: No ID Found