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Nature Oct 2023Scientists have been trying to identify every gene in the human genome since the initial draft was published in 2001. In the years since, much progress has been made in... (Review)
Review
Scientists have been trying to identify every gene in the human genome since the initial draft was published in 2001. In the years since, much progress has been made in identifying protein-coding genes, currently estimated to number fewer than 20,000, with an ever-expanding number of distinct protein-coding isoforms. Here we review the status of the human gene catalogue and the efforts to complete it in recent years. Beside the ongoing annotation of protein-coding genes, their isoforms and pseudogenes, the invention of high-throughput RNA sequencing and other technological breakthroughs have led to a rapid growth in the number of reported non-coding RNA genes. For most of these non-coding RNAs, the functional relevance is currently unclear; we look at recent advances that offer paths forward to identifying their functions and towards eventually completing the human gene catalogue. Finally, we examine the need for a universal annotation standard that includes all medically significant genes and maintains their relationships with different reference genomes for the use of the human gene catalogue in clinical settings.
Topics: Humans; Genome, Human; Molecular Sequence Annotation; Protein Isoforms; Human Genome Project; Genes; Pseudogenes; RNA
PubMed: 37794265
DOI: 10.1038/s41586-023-06490-x -
Brain : a Journal of Neurology Sep 2023Chronic pain affects millions of people worldwide and new treatments are needed urgently. One way to identify novel analgesic strategies is to understand the biological...
Chronic pain affects millions of people worldwide and new treatments are needed urgently. One way to identify novel analgesic strategies is to understand the biological dysfunctions that lead to human inherited pain insensitivity disorders. Here we report how the recently discovered brain and dorsal root ganglia-expressed FAAH-OUT long non-coding RNA (lncRNA) gene, which was found from studying a pain-insensitive patient with reduced anxiety and fast wound healing, regulates the adjacent key endocannabinoid system gene FAAH, which encodes the anandamide-degrading fatty acid amide hydrolase enzyme. We demonstrate that the disruption in FAAH-OUT lncRNA transcription leads to DNMT1-dependent DNA methylation within the FAAH promoter. In addition, FAAH-OUT contains a conserved regulatory element, FAAH-AMP, that acts as an enhancer for FAAH expression. Furthermore, using transcriptomic analyses in patient-derived cells we have uncovered a network of genes that are dysregulated from disruption of the FAAH-FAAH-OUT axis, thus providing a coherent mechanistic basis to understand the human phenotype observed. Given that FAAH is a potential target for the treatment of pain, anxiety, depression and other neurological disorders, this new understanding of the regulatory role of the FAAH-OUT gene provides a platform for the development of future gene and small molecule therapies.
Topics: Humans; RNA, Long Noncoding; Pain; Analgesics; Ganglia, Spinal
PubMed: 37222214
DOI: 10.1093/brain/awad098 -
Nature Sep 2023The prevalence of highly repetitive sequences within the human Y chromosome has prevented its complete assembly to date and led to its systematic omission from genomic...
The prevalence of highly repetitive sequences within the human Y chromosome has prevented its complete assembly to date and led to its systematic omission from genomic analyses. Here we present de novo assemblies of 43 Y chromosomes spanning 182,900 years of human evolution and report considerable diversity in size and structure. Half of the male-specific euchromatic region is subject to large inversions with a greater than twofold higher recurrence rate compared with all other chromosomes. Ampliconic sequences associated with these inversions show differing mutation rates that are sequence context dependent, and some ampliconic genes exhibit evidence for concerted evolution with the acquisition and purging of lineage-specific pseudogenes. The largest heterochromatic region in the human genome, Yq12, is composed of alternating repeat arrays that show extensive variation in the number, size and distribution, but retain a 1:1 copy-number ratio. Finally, our data suggest that the boundary between the recombining pseudoautosomal region 1 and the non-recombining portions of the X and Y chromosomes lies 500 kb away from the currently established boundary. The availability of fully sequence-resolved Y chromosomes from multiple individuals provides a unique opportunity for identifying new associations of traits with specific Y-chromosomal variants and garnering insights into the evolution and function of complex regions of the human genome.
Topics: Humans; Male; Chromosomes, Human, Y; Genome, Human; Genomics; Mutation Rate; Phenotype; Evolution, Molecular; Euchromatin; Pseudogenes; Genetic Variation; Chromosomes, Human, X; Pseudoautosomal Regions
PubMed: 37612510
DOI: 10.1038/s41586-023-06425-6 -
Communications Biology Oct 2023Glioma is the most common primary malignancy of the central nervous system. Glioblastoma (GBM) has the highest degree of malignancy among the gliomas and the strongest...
Glioma is the most common primary malignancy of the central nervous system. Glioblastoma (GBM) has the highest degree of malignancy among the gliomas and the strongest resistance to chemotherapy and radiotherapy. Vasculogenic mimicry (VM) provides tumor cells with a blood supply independent of endothelial cells and greatly restricts the therapeutic effect of anti-angiogenic tumor therapy for glioma patients. Vascular endothelial growth factor receptor 2 (VEGFR2) and vascular endothelial cadherin (VE-cadherin) are currently recognized molecular markers of VM in tumors. In the present study, we show that pseudogene MAPK6P4 deficiency represses VEGFR2 and VE-cadherin protein expression levels, as well as inhibits the proliferation, migration, invasion, and VM development of GBM cells. The MAPK6P4-encoded functional peptide P4-135aa phosphorylates KLF15 at the S238 site, promoting KLF15 protein stability and nuclear entry to promote GBM VM formation. KLF15 was further confirmed as a transcriptional activator of LDHA, where LDHA binds and promotes VEGFR2 and VE-cadherin lactylation, thereby increasing their protein expression. Finally, we used orthotopic and subcutaneous xenografted nude mouse models of GBM to verify the inhibitory effect of the above factors on GBM VM development. In summary, this study may represent new targets for the comprehensive treatment of glioma.
Topics: Animals; Humans; Mice; Cell Line, Tumor; Endothelial Cells; Glioblastoma; Glioma; Neovascularization, Pathologic; Pseudogenes; Vascular Endothelial Growth Factor Receptor-2
PubMed: 37853052
DOI: 10.1038/s42003-023-05438-1 -
Biology Direct Sep 2023Hepatocellular carcinoma (HCC) is one of the most common and challenging cancers in the world. N6-methyladenosine (mA) modification and long non-coding RNAs (lncRNAs)...
BACKGROUND
Hepatocellular carcinoma (HCC) is one of the most common and challenging cancers in the world. N6-methyladenosine (mA) modification and long non-coding RNAs (lncRNAs) play critical roles in the progression of HCC. However, there are few reports on genome-wide screening and functional annotations of mA-methylated lncRNAs in HCC.
METHODS
The expression levels of mA methyltransferase METTL3 and the association with the prognosis in HCC were determined by RT-qPCR, public dataset platforms. Then, RNA-seq, Pearson correlation analysis, MeRIP-qPCR, RNA half-life assay, gene site-directed mutation, RIP assay and RT-qPCR analysis were employed to determine the downstream target of METTL3 in HCC. Subsequently, the expression levels and roles of lncRNA glucosylceramidase beta pseudogene 1 (GBAP1) in HCC were determined by Kaplan-meier curves, RT-qPCR, in vitro functional experiments and in vivo tumorigenesis and lung metastasis models. Then, the downstream target and pathway of GBAP1 were explored by GO biological process, KEGG pathway enrichment, luciferase reporter assay, RIP assay and rescue experiments and so on.
RESULTS
METTL3 was upregulated in HCC and closely related to HCC prognosis. And METTL3 induced GBAP1 expression by acting as the mA writer of GBAP1 and IGF2BP2 worked as its mA reader. Clinically, GBAP1 expression was significantly associated with tumor size, venous infiltration, TNM stage and prognosis of HCC, Functionally, GBAP1 promoted HCC metastasis and growth both in vitro and in vivo. Furthermore, GBAP1 acted as the molecular sponge for miR-22-3p to increase the expression of bone morphogenetic protein receptor type 1A (BMPR1A), which then activated BMP/SMAD pathway in HCC cells.
CONCLUSIONS
Our findings demonstrated that METTL3-induced GBAP1 promoted migration, invasion and proliferation of HCC cells via GBAP1/miR-22-3p/BMPR1A/SMAD axis. GBAP1 could be a potential prognosis indicator and therapeutic target for HCC.
Topics: Humans; Carcinoma, Hepatocellular; RNA, Long Noncoding; Liver Neoplasms; Carcinogenesis; MicroRNAs; Methyltransferases; RNA-Binding Proteins
PubMed: 37658413
DOI: 10.1186/s13062-023-00409-2 -
Epigenetics Dec 2023Pancreatic adenocarcinoma is one of the leading lethal human cancer types and is notorious for its poor prognosis. A series of bioinformatic analyses and experimental...
Pancreatic adenocarcinoma is one of the leading lethal human cancer types and is notorious for its poor prognosis. A series of bioinformatic analyses and experimental validations were employed to explore the role and mechanism of pseudogene-derived RNAs in pancreatic adenocarcinoma. Consequently, a total of 13 upregulated and 7 downregulated pseudogene-derived RNAs in pancreatic adenocarcinoma were identified. Survival analysis revealed a statistically predictive role of AK4P1 for unfavourable prognosis of patients with pancreatic adenocarcinoma. Subcellular location analysis indicated that AK4P1 was mainly located in cytoplasm, in which AK4P1 might competitively bind to tumour suppressive miR-375 in pancreatic adenocarcinoma. Further analysis showed that SP1 was a potential downstream target gene of miR-375 in pancreatic adenocarcinoma. Intriguingly, expression determination validated that SP1 could positively regulate AK4P1 levels in pancreatic adenocarcinoma. Finally, AK4P1 might also exert its effects by interacting with oncogenic parental gene AK4 in pancreatic adenocarcinoma. Conclusively, the present study elucidated a key regulatory loop AK4P1/miR-375/SP1 in pancreatic adenocarcinoma.
Topics: Humans; Adenocarcinoma; Cell Line, Tumor; Cell Proliferation; DNA Methylation; Gene Expression Regulation, Neoplastic; MicroRNAs; Pancreatic Neoplasms; Prognosis; Sp1 Transcription Factor; Adenylate Kinase
PubMed: 36476264
DOI: 10.1080/15592294.2022.2148433 -
Cancers Aug 2023Pseudogenes are duplicates of protein-coding genes that have accumulated multiple detrimental alterations, rendering them unable to produce the protein they encode.... (Review)
Review
Pseudogenes are duplicates of protein-coding genes that have accumulated multiple detrimental alterations, rendering them unable to produce the protein they encode. Initially disregarded as "junk DNA" due to their perceived lack of functionality, research on their biological roles has been hindered by this assumption. Nevertheless, recent focus has shifted towards these molecules due to their abnormal expression in cancer phenotypes. In this review, our objective is to provide a thorough overview of the current understanding of pseudogene formation, the mechanisms governing their expression, and the roles they may play in promoting tumorigenesis.
PubMed: 37627052
DOI: 10.3390/cancers15164024 -
International Journal of Biological... 2023Non-small cell lung cancer (NSCLC) is a highly lethal disease worldwide. We found the pseudogene-derived lncRNA PTTG3P is upregulated in NSCLC and associated with larger...
Non-small cell lung cancer (NSCLC) is a highly lethal disease worldwide. We found the pseudogene-derived lncRNA PTTG3P is upregulated in NSCLC and associated with larger tumor size, advanced staging, and poor prognosis. This study investigated the oncogenic roles and mechanisms of PTTG3P in NSCLC. We demonstrate that PTTG3P promoted NSCLC cell proliferation, migration, tumorigenesis, and metastasis while inhibiting apoptosis and . Mechanistically, PTTG3P formed an RNA-protein complex with ILF3 to maintain MAP2K6 and E2F1 mRNA stability, two oncogenic factors involved in NSCLC progression. RNA-seq revealed MAP2K6 and E2F1 were downregulated upon PTTG3P knockdown. RIP and RNA stability assays showed PTTG3P/ILF3 interaction stabilized MAP2K6 and E2F1 transcripts. Interestingly, E2F1 transcriptionally upregulated PTTG3P by binding its promoter, forming a positive feedback loop. Knockdown of E2F1 or PTTG3P attenuated their mutual regulatory effects on cell growth and migration. Thus, a PTTG3P/ILF3/E2F1 axis enhances oncogene expression to promote NSCLC pathogenesis. Our study reveals PTTG3P exerts oncogenic functions in NSCLC via mRNA stabilization and a feedback loop, highlighting its potential as a prognostic biomarker and therapeutic target.
Topics: Humans; RNA, Long Noncoding; Carcinoma, Non-Small-Cell Lung; Feedback; Lung Neoplasms; Cell Transformation, Neoplastic; Carcinogenesis; RNA Stability; Nuclear Factor 90 Proteins; E2F1 Transcription Factor
PubMed: 37705754
DOI: 10.7150/ijbs.81738 -
Frontiers in Genetics 2023Classical-like Ehlers-Danlos syndrome (clEDS) is an autosomal recessive disorder caused by complete absence of tenascin-X resulting from biallelic variation in . Thus...
Classical-like Ehlers-Danlos syndrome (clEDS) is an autosomal recessive disorder caused by complete absence of tenascin-X resulting from biallelic variation in . Thus far, 50 patients from 43 families with biallelic variants have been identified. Accurate detection of variants is challenging because of the presence of the pseudogene , which can undergo non-allelic homologous recombination. Therefore, we designed a genetic screening system that is performed using similar operations to other next-generation sequencing (NGS) panel analyses and can be applied to accurately detect variants and the recombination of -derived sequences into . Using this system, we identified biallelic variants in nine unrelated clEDS patients. -derived variations were found in >75% of the current cohort, comparable to previous reports. The current cohort generally exhibited similar clinical features to patients in previous reports, but had a higher frequency of gastrointestinal complications (e.g., perforation, diverticulitis, gastrointestinal bleeding, intestinal obstruction, rectal/anal prolapse, and gallstones). This report is the first to apply an NGS-based screening for variants and represents the third largest cohort of clEDS, highlighting the importance of increasing awareness of the risk of gastrointestinal complications.
PubMed: 37712068
DOI: 10.3389/fgene.2023.1234804