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Proliferating cells known as neoblasts include pluripotent stem cells (PSCs) that sustain tissue homeostasis and regeneration of lost body parts in planarians. However, the lack of markers to prospectively identify and isolate these adult PSCs has significantly hampered their characterization. We used single-cell RNA sequencing (scRNA-seq) and single-cell transplantation to address this long-standing issue. Large-scale scRNA-seq of sorted neoblasts unveiled a novel subtype of neoblast (Nb2) characterized by high levels of PIWI-1 mRNA and protein and marked by a conserved cell-surface protein-coding gene, tetraspanin 1 (tspan-1). tspan-1-positive cells survived sub-lethal irradiation, underwent clonal expansion to repopulate whole animals, and when purified with an anti-TSPAN-1 antibody, rescued the viability of lethally irradiated animals after single-cell transplantation. The first prospective isolation of an adult PSC bridges a conceptual dichotomy between functionally and molecularly defined neoblasts, shedding light on mechanisms governing in vivo pluripotency and a source of regeneration in animals. VIDEO ABSTRACT.
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Proteínas Argonautas/metabolismo , Proteínas del Helminto/metabolismo , Planarias/fisiología , Tetraspaninas/metabolismo , Animales , Proteínas Argonautas/antagonistas & inhibidores , Proteínas Argonautas/genética , Ciclo Celular/efectos de la radiación , Regulación de la Expresión Génica , Proteínas del Helminto/antagonistas & inhibidores , Proteínas del Helminto/genética , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Células Madre Pluripotentes/trasplante , Análisis de Componente Principal , Interferencia de ARN , ARN Bicatenario/metabolismo , ARN de Helminto/química , ARN de Helminto/aislamiento & purificación , ARN de Helminto/metabolismo , Regeneración/genética , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Tetraspaninas/genética , Irradiación Corporal TotalRESUMEN
The scarcity of tissue-specific stem cells and the complexity of their surrounding environment have made molecular characterization of these cells particularly challenging. Through single-cell transcriptome and weighted gene co-expression network analysis (WGCNA), we uncovered molecular properties of CD133(+)/GFAP(-) ependymal (E) cells in the adult mouse forebrain neurogenic zone. Surprisingly, prominent hub genes of the gene network unique to ependymal CD133(+)/GFAP(-) quiescent cells were enriched for immune-responsive genes, as well as genes encoding receptors for angiogenic factors. Administration of vascular endothelial growth factor (VEGF) activated CD133(+) ependymal neural stem cells (NSCs), lining not only the lateral but also the fourth ventricles and, together with basic fibroblast growth factor (bFGF), elicited subsequent neural lineage differentiation and migration. This study revealed the existence of dormant ependymal NSCs throughout the ventricular surface of the CNS, as well as signals abundant after injury for their activation.
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Epéndimo/citología , Células-Madre Neurales/metabolismo , Antígeno AC133 , Animales , Antígenos CD/metabolismo , Diferenciación Celular , Movimiento Celular , Epéndimo/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Glicoproteínas/metabolismo , Ratones , Células-Madre Neurales/citología , Péptidos/metabolismo , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
The gene encoding PTEN is one of the most frequently mutated tumor suppressor-encoding genes in human cancer. While PTEN's function in tumor suppression is well established, its relationship to anti-microbial immunity remains unknown. Here we found a pivotal role for PTEN in the induction of type I interferon, the hallmark of antiviral innate immunity, that was independent of the pathway of the kinases PI(3)K and Akt. PTEN controlled the import of IRF3, a master transcription factor responsible for IFN-ß production, into the nucleus. We further identified a PTEN-controlled negative phosphorylation site at Ser97 of IRF3 and found that release from this negative regulation via the phosphatase activity of PTEN was essential for the activation of IRF3 and its import into the nucleus. Our study identifies crosstalk between PTEN and IRF3 in tumor suppression and innate immunity.
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Inmunidad Innata/inmunología , Factor 3 Regulador del Interferón/inmunología , Interferón Tipo I/inmunología , Fosfohidrolasa PTEN/inmunología , Infecciones por Respirovirus/inmunología , Infecciones por Rhabdoviridae/inmunología , Animales , Línea Celular , Línea Celular Tumoral , Núcleo Celular , Proliferación Celular , Citocinas/inmunología , Células Dendríticas/inmunología , Electroforesis en Gel de Poliacrilamida , Técnica del Anticuerpo Fluorescente , Técnicas de Transferencia de Gen , Células HEK293 , Humanos , Immunoblotting , Inmunoprecipitación , Factor 3 Regulador del Interferón/genética , Factor 7 Regulador del Interferón/genética , Células MCF-7 , Macrófagos/inmunología , Espectrometría de Masas , Ratones , Microscopía Confocal , Mutagénesis Sitio-Dirigida , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Virus Sendai , VesiculovirusRESUMEN
Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects1-4. For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a major role in its mechanism of action4,5; however, the direct molecular target of metformin remains unknown. Here we show that clinically relevant concentrations of metformin inhibit the lysosomal proton pump v-ATPase, which is a central node for AMPK activation following glucose starvation6. We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase7, as a binding partner of metformin with a dissociation constant at micromolar levels. Metformin-bound PEN2 forms a complex with ATP6AP1, a subunit of the v-ATPase8, which leads to the inhibition of v-ATPase and the activation of AMPK without effects on cellular AMP levels. Knockout of PEN2 or re-introduction of a PEN2 mutant that does not bind ATP6AP1 blunts AMPK activation. In vivo, liver-specific knockout of Pen2 abolishes metformin-mediated reduction of hepatic fat content, whereas intestine-specific knockout of Pen2 impairs its glucose-lowering effects. Furthermore, knockdown of pen-2 in Caenorhabditis elegans abrogates metformin-induced extension of lifespan. Together, these findings reveal that metformin binds PEN2 and initiates a signalling route that intersects, through ATP6AP1, the lysosomal glucose-sensing pathway for AMPK activation. This ensures that metformin exerts its therapeutic benefits in patients without substantial adverse effects.
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Hipoglucemiantes , Metformina , ATPasas de Translocación de Protón Vacuolares , Proteínas Quinasas Activadas por AMP/metabolismo , Adenosina Trifosfatasas/metabolismo , Secretasas de la Proteína Precursora del Amiloide , Animales , Caenorhabditis elegans/metabolismo , Diabetes Mellitus/tratamiento farmacológico , Glucosa/metabolismo , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/metabolismo , Hipoglucemiantes/farmacología , Lisosomas/metabolismo , Proteínas de la Membrana , Metformina/agonistas , Metformina/metabolismo , Metformina/farmacología , ATPasas de Translocación de Protón Vacuolares/metabolismoRESUMEN
Variability in quantitative traits has clinical, ecological, and evolutionary significance. Most genetic variants identified for complex quantitative traits have only a detectable effect on the mean of trait. We have developed the mean-variance test (MVtest) to simultaneously model the mean and log-variance of a quantitative trait as functions of genotypes and covariates by using estimating equations. The advantages of MVtest include the facts that it can detect effect modification, that multiple testing can follow conventional thresholds, that it is robust to non-normal outcomes, and that association statistics can be meta-analyzed. In simulations, we show control of type I error of MVtest over several alternatives. We identified 51 and 37 previously unreported associations for effects on blood-pressure variance and mean, respectively, in the UK Biobank. Transcriptome-wide association studies revealed 633 significant unique gene associations with blood-pressure mean variance. MVtest is broadly applicable to studies of complex quantitative traits and provides an important opportunity to detect novel loci.
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Presión Sanguínea , Estudio de Asociación del Genoma Completo , Sitios de Carácter Cuantitativo , Humanos , Presión Sanguínea/genética , Polimorfismo de Nucleótido Simple , Modelos Genéticos , Genotipo , Variación Genética , Simulación por Computador , FenotipoRESUMEN
Although DNA N 6-adenine methylation (6mA) is best known in prokaryotes, its presence in eukaryotes has recently generated great interest. Biochemical and genetic evidence supports that AMT1, an MT-A70 family methyltransferase (MTase), is crucial for 6mA deposition in unicellular eukaryotes. Nonetheless, the 6mA transmission mechanism remains to be elucidated. Taking advantage of single-molecule real-time circular consensus sequencing (SMRT CCS), here we provide definitive evidence for semiconservative transmission of 6mA in Tetrahymena thermophila In wild-type (WT) cells, 6mA occurs at the self-complementary ApT dinucleotide, mostly in full methylation (full-6mApT); after DNA replication, hemi-methylation (hemi-6mApT) is transiently present on the parental strand, opposite to the daughter strand readily labeled by 5-bromo-2'-deoxyuridine (BrdU). In ΔAMT1 cells, 6mA predominantly occurs as hemi-6mApT. Hemi-to-full conversion in WT cells is fast, robust, and processive, whereas de novo methylation in ΔAMT1 cells is slow and sporadic. In Tetrahymena, regularly spaced 6mA clusters coincide with the linker DNA of nucleosomes arrayed in the gene body. Importantly, in vitro methylation of human chromatin by the reconstituted AMT1 complex recapitulates preferential targeting of hemi-6mApT sites in linker DNA, supporting AMT1's intrinsic and autonomous role in maintenance methylation. We conclude that 6mA is transmitted by a semiconservative mechanism: full-6mApT is split by DNA replication into hemi-6mApT, which is restored to full-6mApT by AMT1-dependent maintenance methylation. Our study dissects AMT1-dependent maintenance methylation and AMT1-independent de novo methylation, reveals a 6mA transmission pathway with a striking similarity to 5-methylcytosine (5mC) transmission at the CpG dinucleotide, and establishes 6mA as a bona fide eukaryotic epigenetic mark.
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Adenina , Metilación de ADN , Tetrahymena thermophila , Tetrahymena thermophila/genética , Tetrahymena thermophila/metabolismo , Adenina/metabolismo , Adenina/análogos & derivados , Replicación del ADN , ADN Protozoario/genética , ADN Protozoario/metabolismoRESUMEN
Living tissues display fluctuations-random spatial and temporal variations of tissue properties around their reference values-at multiple scales. It is believed that such fluctuations may enable tissues to sense their state or their size. Recent theoretical studies developed specific models of fluctuations in growing tissues and predicted that fluctuations of growth show long-range correlations. Here, we elaborated upon these predictions and we tested them using experimental data. We first introduced a minimal model for the fluctuations of any quantity that has some level of temporal persistence or memory, such as concentration of a molecule, local growth rate, or mechanical property. We found that long-range correlations are generic, applying to any such quantity, and that growth couples temporal and spatial fluctuations, through a mechanism that we call "fluctuation stretching"-growth enlarges the length scale of variation of this quantity. We then analyzed growth data from sepals of the model plant Arabidopsis and we quantified spatial and temporal fluctuations of cell growth using the previously developed cellular Fourier transform. Growth appears to have long-range correlations. We compared different genotypes and growth conditions: mutants with lower or higher response to mechanical stress have lower temporal correlations and longer-range spatial correlations than wild-type plants. Finally, we used theoretical predictions to merge experimental data from all conditions and developmental stages into a unifying curve, validating the notion that temporal and spatial fluctuations are coupled by growth. Altogether, our work reveals kinematic constraints on spatiotemporal fluctuations that have an impact on the robustness of morphogenesis.
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Arabidopsis , Modelos Biológicos , Morfogénesis , Arabidopsis/crecimiento & desarrollo , Arabidopsis/genética , Arabidopsis/metabolismo , Arabidopsis/fisiología , Flores/crecimiento & desarrollo , Flores/genéticaRESUMEN
Immune-mediated necrotizing myopathy (IMNM) is an autoimmune disorder associated with the presence of autoantibodies, characterized by severe clinical presentation with rapidly progressive muscular weakness and elevated levels of creatine kinase, while traditional pharmacological approaches possess varying and often limited effects. Considering the pathogenic role of autoantibodies, chimeric antigen receptor (CAR)-T cells targeting B cell maturation antigen (BCMA) have emerged as a promising therapeutic strategy. We reported here a patient with anti-signal recognition particle IMNM refractory to multiple available therapies, who was treated with BCMA-targeting CAR-T cells, exhibited favorable safety profiles, sustained reduction in pathogenic autoantibodies, and persistent clinical improvements over 18 mo. Longitudinal single-cell RNA, B cell receptor, T cell receptor sequencing analysis presented the normalization of immune microenvironment after CAR-T cell infusion, including reconstitution of B cell lineages, replacement of T cell subclusters, and suppression of overactivated immune cells. Analysis on characteristics of CAR-T cells in IMNM demonstrated a more active expansion of CD8+ CAR-T cells, with a dynamic phenotype shifting pattern similar in CD4+ and CD8+ CAR-T cells. A comparison of CD8+ CAR-T cells in patients with IMNM and those with malignancies collected at different timepoints revealed a more NK-like phenotype with enhanced tendency of cell death and neuroinflammation and inhibited proliferating ability of CD8+ CAR-T cells in IMNM while neuroinflammation might be the distinct characteristics. Further studies are warranted to define the molecular features of CAR-T cells in autoimmunity and to seek higher efficiency and longer persistence of CAR-T cells in treating autoimmune disorders.
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Enfermedades Autoinmunes , Mieloma Múltiple , Enfermedades Musculares , Receptores Quiméricos de Antígenos , Humanos , Mieloma Múltiple/tratamiento farmacológico , Antígeno de Maduración de Linfocitos B , Enfermedades Neuroinflamatorias , Inmunoterapia Adoptiva , Enfermedades Autoinmunes/terapia , Autoanticuerpos , Enfermedades Musculares/terapia , Análisis de la Célula Individual , Tratamiento Basado en Trasplante de Células y Tejidos , Microambiente TumoralRESUMEN
Cryptophyte plastids originated from a red algal ancestor through secondary endosymbiosis. Cryptophyte photosystem I (PSI) associates with transmembrane alloxanthin-chlorophyll a/c proteins (ACPIs) as light-harvesting complexes (LHCs). Here, we report the structure of the photosynthetic PSI-ACPI supercomplex from the cryptophyte Chroomonas placoidea at 2.7-Å resolution obtained by crygenic electron microscopy. Cryptophyte PSI-ACPI represents a unique PSI-LHCI intermediate in the evolution from red algal to diatom PSI-LHCI. The PSI-ACPI supercomplex is composed of a monomeric PSI core containing 14 subunits, 12 of which originated in red algae, 1 diatom PsaR homolog, and an additional peptide. The PSI core is surrounded by 14 ACPI subunits that form 2 antenna layers: an inner layer with 11 ACPIs surrounding the PSI core and an outer layer containing 3 ACPIs. A pigment-binding subunit that is not present in any other previously characterized PSI-LHCI complexes, ACPI-S, mediates the association and energy transfer between the outer and inner ACPIs. The extensive pigment network of PSI-ACPI ensures efficient light harvesting, energy transfer, and dissipation. Overall, the PSI-LHCI structure identified in this study provides a framework for delineating the mechanisms of energy transfer in cryptophyte PSI-LHCI and for understanding the evolution of photosynthesis in the red lineage, which occurred via secondary endosymbiosis.
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Diatomeas , Complejos de Proteína Captadores de Luz , Complejos de Proteína Captadores de Luz/metabolismo , Clorofila A/metabolismo , Complejo de Proteína del Fotosistema I/metabolismo , Fotosíntesis , Transferencia de Energía , Diatomeas/metabolismoRESUMEN
Chromatin accessibility profiles at single cell resolution can reveal cell type-specific regulatory programs, help dissect highly specialized cell functions and trace cell origin and evolution. Accurate cell type assignment is critical for effectively gaining biological and pathological insights, but is difficult in scATAC-seq. Hence, by extensively reviewing the literature, we designed scATAC-Ref (https://bio.liclab.net/scATAC-Ref/), a manually curated scATAC-seq database aimed at providing a comprehensive, high-quality source of chromatin accessibility profiles with known cell labels across broad cell types. Currently, scATAC-Ref comprises 1 694 372 cells with known cell labels, across various biological conditions, >400 cell/tissue types and five species. We used uniform system environment and software parameters to perform comprehensive downstream analysis on these chromatin accessibility profiles with known labels, including gene activity score, TF enrichment score, differential chromatin accessibility regions, pathway/GO term enrichment analysis and co-accessibility interactions. The scATAC-Ref also provided a user-friendly interface to query, browse and visualize cell types of interest, thereby providing a valuable resource for exploring epigenetic regulation in different tissues and cell types.
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Secuenciación de Inmunoprecipitación de Cromatina , Cromatina , Bases de Datos Genéticas , Análisis de la Célula Individual , Cromatina/genética , Epigénesis Genética , Humanos , AnimalesRESUMEN
Transforming growth factor-ß (TGF-ß) and Hippo signaling are two critical pathways engaged in cancer progression by regulating both oncogenes and tumor suppressors, yet how the two pathways coordinately exert their functions in the development of hepatocellular carcinoma (HCC) remains elusive. In this study, we firstly conducted an integrated analysis of public liver cancer databases and our experimental TGF-ß target genes, identifying CYR61 as a pivotal candidate gene relating to HCC development. The expression of CYR61 is downregulated in clinical HCC tissues and cell lines than that in the normal counterparts. Evidence revealed that CYR61 is a direct target gene of TGF-ß in liver cancer cells. In addition, TGF-ß-stimulated Smad2/3 and the Hippo pathway downstream effectors YAP and TEAD4 can form a protein complex on the promoter of CYR61, thereby activating the promoter activity and stimulating CYR61 gene transcription in a collaborative manner. Functionally, depletion of CYR61 enhanced TGF-ß- or YAP-mediated growth and migration of liver cancer cells. Consistently, ectopic expression of CYR61 was capable of impeding TGF-ß- or YAP-induced malignant transformation of HCC cells in vitro and attenuating HCC xenograft growth in nude mice. Finally, transcriptomic analysis indicates that CYR61 can elicit an antitumor program in liver cancer cells. Together, these results add new evidence for the crosstalk between TGF-ß and Hippo signaling and unveil an important tumor suppressor function of CYR61 in liver cancer.
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Carcinoma Hepatocelular , Proteína 61 Rica en Cisteína , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , Factor de Crecimiento Transformador beta , Proteínas Señalizadoras YAP , Animales , Humanos , Ratones , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Movimiento Celular , Proteína 61 Rica en Cisteína/metabolismo , Proteína 61 Rica en Cisteína/genética , Minería de Datos , Regulación Neoplásica de la Expresión Génica/genética , Vía de Señalización Hippo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Ratones Desnudos , Regiones Promotoras Genéticas , Transducción de Señal/genética , Proteína Smad2/metabolismo , Proteína Smad2/genética , Proteína smad3/metabolismo , Proteína smad3/genética , Factores de Transcripción de Dominio TEA/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/genética , Regulación hacia Arriba , Proteínas Señalizadoras YAP/metabolismo , Proteínas Señalizadoras YAP/genéticaRESUMEN
Dynamic chromatin organization instantly influences DNA accessibility through modulating local macromolecular density and interactions, driving changes in transcription activities. Chromatin dynamics have been reported to be locally confined but contribute to coherent chromatin motion across the entire nucleus. However, the regulation of dynamics, nuclear orientation and compaction of subregions along a single chromosome are not well-understood. We used CRISPR-based real-time single-particle tracking and polymer models to characterize the dynamics of specific genomic loci and determine compaction levels of large human chromosomal domains. Our studies showed that chromosome compaction changed during interphase and that compactions of two arms on chromosome 19 were different. The dynamics of genomic loci were subdiffusive and dependent on chromosome regions and transcription states. Surprisingly, the correlation between locus-dependent nuclear localization and mobility was negligible. Strong tethering interactions detected at the pericentromeric region implies local condensation or associations with organelles within local nuclear microenvironments, such as chromatin-nuclear body association. Based on our findings, we propose a 'guided radial model' for the nuclear orientation of the long arm of chromosome 19.
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Núcleo Celular , Cromatina , Humanos , Núcleo Celular/fisiología , Cromosomas Humanos , InterfaseRESUMEN
[This corrects the article DOI: 10.1371/journal.ppat.1011320.].
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Viral seasonality in the aquaculture industry is an important scientific issue for decades. While the molecular mechanisms underpinning the temperature-dependent pathogenesis of aquatic viral diseases remain largely unknown. Here we report that temperature-dependent activation of IL6-STAT3 signaling was exploited by grass carp reovirus (GCRV) to promote viral entry via increasing the expression of heat shock protein 90 (HSP90). Deploying GCRV infection as a model system, we discovered that GCRV induces the IL6-STAT3-HSP90 signaling activation to achieve temperature-dependent viral entry. Further biochemical and microscopic analyses revealed that the major capsid protein VP7 of GCRV interacted with HSP90 and relevant membrane-associated proteins to boost viral entry. Accordingly, exogenous expression of either IL6, HSP90, or VP7 in cells increased GCRV entry in a dose-dependent manner. Interestingly, other viruses (e.g., koi herpesvirus, Rhabdovirus carpio, Chinese giant salamander iridovirus) infecting ectothermic vertebrates have evolved a similar mechanism to promote their infection. This work delineates a molecular mechanism by which an aquatic viral pathogen exploits the host temperature-related immune response to promote its entry and replication, instructing us on new ways to develop targeted preventives and therapeutics for aquaculture viral diseases.
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Carpas , Enfermedades de los Peces , Orthoreovirus , Infecciones por Reoviridae , Reoviridae , Animales , Internalización del Virus , Interleucina-6/metabolismo , Infecciones por Reoviridae/metabolismo , Proteínas de la Cápside/metabolismo , Anticuerpos Antivirales/metabolismoRESUMEN
The carboxysome is a natural proteinaceous organelle for carbon fixation in cyanobacteria and chemoautotrophs. It comprises hundreds of protein homologs that self-assemble to form a polyhedral shell structure to sequester cargo enzymes, ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) and carbonic anhydrases. How these protein components assemble to construct a functional carboxysome is a central question in not only understanding carboxysome structure and function but also synthetic engineering of carboxysomes for biotechnological applications. Here, we determined the structure of the chaperone protein CcmS, which has recently been identified to be involved in ß-carboxysome assembly, and its interactions with ß-carboxysome proteins. The crystal structure at 1.99 Å resolution reveals CcmS from Nostoc sp. PCC 7120 forms a homodimer, and each CcmS monomer consists of five α-helices and four ß-sheets. Biochemical assays indicate that CcmS specifically interacts with the C-terminal extension of the carboxysome shell protein CcmK1, but not the shell protein homolog CcmK2 or the carboxysome scaffolding protein CcmM. Moreover, we solved the structure of a stable complex of CcmS and the C-terminus of CcmK1 at 1.67 Å resolution and unveiled how the CcmS dimer interacts with the C-terminus of CcmK1. These findings allowed us to propose a model to illustrate CcmS-mediated ß-carboxysome assembly by interacting with CcmK1 at the outer shell surface. Collectively, our study provides detailed insights into the accessory factors that drive and regulate carboxysome assembly, thereby improving our knowledge of carboxysome structure, function, and bioengineering.
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OBJECTIVE: This study aimed to identify candidate loci and genes related to sleep disturbances in depressed individuals and clarify the co-occurrence of sleep disturbances and depression from the genetic perspective. METHODS: The study subjects (including 58,256 self-reported depressed individuals and 6,576 participants with PHQ-9 score ≥ 10, respectively) were collected from the UK Biobank, which were determined based on the Patient Health Questionnaire (PHQ-9) and self-reported depression status, respectively. Sleep related traits included chronotype, insomnia, snoring and daytime dozing. Genome-wide association studies (GWASs) of sleep related traits in depressed individuals were conducted by PLINK 2.0 adjusting age, sex, Townsend deprivation index and 10 principal components as covariates. The CAUSALdb database was used to explore the mental traits associated with the candidate genes identified by the GWAS. RESULTS: GWAS detected 15 loci significantly associated with chronotype in the subjects with self-reported depression, such as rs12736689 at RNASEL (P = 1.00 × 10- 09), rs509476 at RGS16 (P = 1.58 × 10- 09) and rs1006751 at RFX4 (P = 1.54 × 10- 08). 9 candidate loci were identified in the subjects with PHQ-9 ≥ 10, of which 2 loci were associated with insomnia such as rs115379847 at EVC2 (P = 3.50 × 10- 08), and 7 loci were associated with daytime dozing, such as rs140876133 at SMYD3 (P = 3.88 × 10- 08) and rs139156969 at ROBO2 (P = 3.58 × 10- 08). Multiple identified genes, such as RNASEL, RGS16, RFX4 and ROBO2 were reported to be associated with chronotype, depression or cognition in previous studies. CONCLUSION: Our study identified several candidate genes related to sleep disturbances in depressed individuals, which provided new clues for understanding the biological mechanism underlying the co-occurrence of depression and sleep disorders.
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Depresión , Estudio de Asociación del Genoma Completo , Trastornos del Sueño-Vigilia , Humanos , Masculino , Femenino , Trastornos del Sueño-Vigilia/genética , Persona de Mediana Edad , Depresión/genética , Polimorfismo de Nucleótido Simple/genética , Predisposición Genética a la Enfermedad , Anciano , AdultoRESUMEN
The maintenance of lysosome homeostasis is crucial for cell growth. Lysosome-dependent degradation and metabolism sustain tumor cell survival. Here, we demonstrate that CCDC50 serves as a lysophagy receptor, promoting tumor progression and invasion by controlling lysosomal integrity and renewal. CCDC50 monitors lysosomal damage, recognizes galectin-3 and K63-linked polyubiquitination on damaged lysosomes, and specifically targets them for autophagy-dependent degradation. CCDC50 deficiency causes the accumulation of ruptured lysosomes, impaired autophagic flux, and superfluous reactive oxygen species, consequently leading to cell death and tumor suppression. CCDC50 expression is associated with malignancy, progression to metastasis, and poor overall survival in human melanoma. Targeting CCDC50 suppresses tumor growth and lung metastasis, and enhances the effect of BRAFV600E inhibition. Thus, we demonstrate critical roles of CCDC50-mediated clearance of damaged lysosomes in supporting tumor growth, hereby identifying a potential therapeutic target of melanoma.
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MicroRNAs (miRNAs) are small non-coding RNAs first discovered in Caenorhabditis elegans. The let-7 miRNA is highly conserved in sequence, biogenesis and function from C. elegans to humans. During miRNA biogenesis, XPO5-mediated nuclear export of pre-miRNAs is a rate-limiting step and, therefore, might be critical for the quantitative control of miRNA levels, yet little is known about how this is regulated. Here we show a novel role for lipid kinase PPK-1/PIP5K1A (phosphatidylinositol-4-phosphate 5-kinase) in regulating miRNA levels. We found that C. elegans PPK-1 functions in the lin-28/let-7 heterochronic pathway, which regulates the strict developmental timing of seam cells. In C. elegans and human cells, PPK-1/PIP5K1A regulates let-7 miRNA levels. We investigated the mechanism further in human cells and show that PIP5K1A interacts with nuclear export protein XPO5 in the nucleus to regulate mature miRNA levels by blocking the binding of XPO5 to pre-let-7 miRNA. Furthermore, we demonstrate that this role for PIP5K1A is kinase-independent. Our study uncovers the novel finding of a direct connection between PIP5K1A and miRNA biogenesis. Given that miRNAs are implicated in multiple diseases, including cancer, this new finding might lead to a novel therapeutic opportunity.
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Carioferinas , MicroARNs , Fosfotransferasas (Aceptor de Grupo Alcohol) , Animales , Humanos , Transporte Activo de Núcleo Celular , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Carioferinas/genética , Carioferinas/metabolismo , Lípidos , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Nucleares/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismoRESUMEN
Super-enhancers (SEs) play an essential regulatory role in various biological processes and diseases through their specific interaction with transcription factors (TFs). Here, we present the release of SEanalysis 2.0 (http://licpathway.net/SEanalysis), an updated version of the SEanalysis web server for the comprehensive analyses of transcriptional regulatory networks formed by SEs, pathways, TFs, and genes. The current version added mouse SEs and further expanded the scale of human SEs, documenting 1 167 518 human SEs from 1739 samples and 550 226 mouse SEs from 931 samples. The SE-related samples in SEanalysis 2.0 were more than five times that in version 1.0, which significantly improved the ability of original SE-related network analyses ('pathway downstream analysis', 'upstream regulatory analysis' and 'genomic region annotation') for understanding context-specific gene regulation. Furthermore, we designed two novel analysis models, 'TF regulatory analysis' and 'Sample comparative analysis' for supporting more comprehensive analyses of SE regulatory networks driven by TFs. Further, the risk SNPs were annotated to the SE regions to provide potential SE-related disease/trait information. Hence, we believe that SEanalysis 2.0 has significantly expanded the data and analytical capabilities of SEs, which helps researchers in an in-depth understanding of the regulatory mechanisms of SEs.
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Elementos de Facilitación Genéticos , Redes Reguladoras de Genes , Programas Informáticos , Factores de Transcripción , Animales , Humanos , Ratones , Regulación de la Expresión Génica , Genómica , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Rechargeable lithium-ion batteries are integral to contemporary energy storage, yet current anode material systems struggle to meet the increasing demand for extended range capabilities. This work introduces a novel composite anode material composed of one-dimensional 2H-phase tin disulfide (SnS2) nanoribbons enclosed within cavities of single-walled carbon nanotubes (SnS2@SWCNTs), achieved through precise atomic engineering. Employing aberration-corrected transmission electron microscopy, we precisely elucidated the crystal structure of SnS2 within the confines of the SWCNTs. This deliberate design effectively addresses the inherent limitations of SnS2 as a lithium-ion anode material, including its low electrical conductivity, considerable volume expansion effects, and unstable solid electrolyte interface membrane. Testing confirmed that SnS2 transforms into the Li5Sn2 alloy phase after full lithiation and back to SnS2 after delithiation, showing excellent reversibility. The composite also benefits from edge effects, improving lithium storage through stronger binding and lower migration barriers, which were supported by calculations. This pioneering work advances high-performance anode materials for applications.