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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 -
Cell Aug 2023Approximately 15% of US adults have circulating levels of uric acid above its solubility limit, which is causally linked to the disease gout. In most mammals, uric acid...
Approximately 15% of US adults have circulating levels of uric acid above its solubility limit, which is causally linked to the disease gout. In most mammals, uric acid elimination is facilitated by the enzyme uricase. However, human uricase is a pseudogene, having been inactivated early in hominid evolution. Though it has long been known that uric acid is eliminated in the gut, the role of the gut microbiota in hyperuricemia has not been studied. Here, we identify a widely distributed bacterial gene cluster that encodes a pathway for uric acid degradation. Stable isotope tracing demonstrates that gut bacteria metabolize uric acid to xanthine or short chain fatty acids. Ablation of the microbiota in uricase-deficient mice causes severe hyperuricemia, and anaerobe-targeted antibiotics increase the risk of gout in humans. These data reveal a role for the gut microbiota in uric acid excretion and highlight the potential for microbiome-targeted therapeutics in hyperuricemia.
Topics: Adult; Animals; Humans; Mice; Gout; Hominidae; Hyperuricemia; Mammals; Urate Oxidase; Uric Acid; Evolution, Molecular
PubMed: 37541197
DOI: 10.1016/j.cell.2023.06.010 -
Arteriosclerosis, Thrombosis, and... Nov 2023Current therapies cannot completely reverse advanced atherosclerosis. High levels of amino acids, induced by Western diet, stimulate mTORC1 (mammalian target of...
BACKGROUND
Current therapies cannot completely reverse advanced atherosclerosis. High levels of amino acids, induced by Western diet, stimulate mTORC1 (mammalian target of rapamycin complex 1)-autophagy defects in macrophages, accelerating atherosclerotic plaque progression. In addition, autophagy-lysosomal dysfunction contributes to plaque necrotic core enlargement and lipid accumulation. Therefore, it is essential to investigate the novel mechanism and molecules to reverse amino acid-mTORC1-autophagy signaling dysfunction in macrophages of patients with advanced atherosclerosis.
METHODS
We observed that Gpr137b-ps (G-protein-coupled receptor 137B, pseudogene) was upregulated in advanced atherosclerotic plaques. The effect of Gpr137b-ps on the progression of atherosclerosis was studied by generating advanced plaques in mice with cardiac-specific knockout of Gpr137b-ps. Bone marrow-derived macrophages and mouse mononuclear macrophage cell line RAW264.7 cells were subjected to starvation or amino acid stimulation to study amino acid-mTORC1-autophagy signaling. Using both gain- and loss-of-function approaches, we explored the mechanism of Gpr137b-ps-regulated autophagy.
RESULTS
Our results demonstrated that Gpr137b-ps deficiency led to enhanced autophagy in macrophages and reduced atherosclerotic lesions, characterized by fewer necrotic cores and less lipid accumulation. Knockdown of Gpr137b-ps increased autophagy and prevented amino acid-induced mTORC1 signaling activation. As the downstream binding protein of Gpr137b-ps, HSC70 (heat shock cognate 70) rescued the impaired autophagy induced by Gpr137b-ps. Furthermore, Gpr137b-ps interfered with the HSC70 binding to G3BP (Ras GTPase-activating protein-binding protein), which tethers the TSC (tuberous sclerosis complex) complex to lysosomes and suppresses mTORC1 signaling. In addition to verifying that the NTF2 (nuclear transport factor 2) domain of G3BP binds to HSC70 by in vitro protein synthesis, we further demonstrated that HSC70 binds to the NTF2 domain of G3BP through its W90-F92 motif by using computational modeling.
CONCLUSIONS
These findings reveal that Gpr137b-ps plays an essential role in the regulation of macrophage autophagy, which is crucial for the progression of advanced atherosclerosis. Gpr137b-ps impairs the interaction of HSC70 with G3BP to regulate amino acid-mTORC1-autophagy signaling, and these results provide a new potential therapeutic direction for the treatment of advanced atherosclerosis.
Topics: Humans; Mice; Animals; RNA, Long Noncoding; Atherosclerosis; Plaque, Atherosclerotic; Macrophages; Mechanistic Target of Rapamycin Complex 1; Autophagy; Amino Acids; Lipids; Mammals
PubMed: 37767704
DOI: 10.1161/ATVBAHA.123.319037 -
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 -
Current Microbiology Jul 2023The genus Liquorilactobacillus is a new genus commonly found in wine and plants. Despite its significance, previous studies on Liquorilactobacillus are primarily focused...
The genus Liquorilactobacillus is a new genus commonly found in wine and plants. Despite its significance, previous studies on Liquorilactobacillus are primarily focused on phenotypic experiments, with limited genome-level studies. This study used comparative genomics to analyze 24 genomes from the genus Liquorilactobacillus, including two novel sequenced strains (IMAU80559 and IMAU80777). A phylogenetic tree of 24 strains was constructed based on 122 core genes and divided into two clades, A and B. Significant differences in GC content were observed between the two clades (P = 10e). Additionally, change revealed to suggests that clade B has more exposure to prophage infection having an upgraded immune system. Further analysis of functional annotation and selective pressure suggests that clade A was subjected to greater selection pressure than B clade (P = 3.9e) and had higher number of functional types annotated than clade B (P = 2.7e), while clade B had a lower number of pseudogenes than clade A (P = 1.9e). The findings suggest that differently prophages and environmental stress may have influenced the common ancestor of clades A and B during evolution, leading to the development of two distinct clades.
Topics: Phylogeny; Genome, Bacterial; Genomics
PubMed: 37420021
DOI: 10.1007/s00284-023-03336-7 -
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