-
Journal of Advanced Research Mar 2022The intestinal tract is a complicated ecosystem with dynamic homeostasis via interaction of intestine and microbiota. Inflammatory bowel disease (IBD) is chronic... (Review)
Review
BACKGROUND
The intestinal tract is a complicated ecosystem with dynamic homeostasis via interaction of intestine and microbiota. Inflammatory bowel disease (IBD) is chronic intestinal inflammation involving dysbiosis of intestinal microenvironment. Extracellular vesicles (EVs), as vital characteristics of cell-cell and cell-organism communication, contribute to homeostasis in intestine. Recently, EVs showed excellent potential for clinical applications in disease diagnoses and therapies.
AIM OF REVIEW
Our current review discusses the modulatory functions of EVs derived from different sources in intestine, especially their effects and applications in IBD clinical therapy. EV-mediated interaction systems between host intestine and microbiota were established to describe possible mechanisms of IBD pathogenesis and its cure.
KEY SCIENTIFIC CONCEPTS OF REVIEW
EVs are excellent vehicles for delivering molecules containing genetic information to recipient cells. Multiple pieces of evidence have illustrated that EVs participate the interaction between host and microbiota in intestinal microenvironment. In inflammatory intestine with dysbiosis of microbiota, EVs as regulators target promoting immune response and microbial reconstruction. EVs-based immunotherapy could be a promising therapeutic approach for the treatment of IBD in the near future.
Topics: Dysbiosis; Extracellular Vesicles; Humans; Inflammatory Bowel Diseases; Intestines; Microbiota
PubMed: 35499059
DOI: 10.1016/j.jare.2021.07.002 -
Nature Reviews. Molecular Cell Biology Apr 2023Membraneless organelles (MLOs) are detected in cells as dots of mesoscopic size. By undergoing phase separation into a liquid-like or gel-like phase, MLOs contribute to... (Review)
Review
Membraneless organelles (MLOs) are detected in cells as dots of mesoscopic size. By undergoing phase separation into a liquid-like or gel-like phase, MLOs contribute to intracellular compartmentalization of specific biological functions. In eukaryotes, dozens of MLOs have been identified, including the nucleolus, Cajal bodies, nuclear speckles, paraspeckles, promyelocytic leukaemia protein (PML) nuclear bodies, nuclear stress bodies, processing bodies (P bodies) and stress granules. MLOs contain specific proteins, of which many possess intrinsically disordered regions (IDRs), and nucleic acids, mainly RNA. Many MLOs contribute to gene regulation by different mechanisms. Through sequestration of specific factors, MLOs promote biochemical reactions by simultaneously concentrating substrates and enzymes, and/or suppressing the activity of the sequestered factors elsewhere in the cell. Other MLOs construct inter-chromosomal hubs by associating with multiple loci, thereby contributing to the biogenesis of macromolecular machineries essential for gene expression, such as ribosomes and spliceosomes. The organization of many MLOs includes layers, which might have different biophysical properties and functions. MLOs are functionally interconnected and are involved in various diseases, prompting the emergence of therapeutics targeting them. In this Review, we introduce MLOs that are relevant to gene regulation and discuss their assembly, internal structure, gene-regulatory roles in transcription, RNA processing and translation, particularly in stress conditions, and their disease relevance.
Topics: Organelles; Biomolecular Condensates; RNA; Gene Expression Regulation; Transcription Factors
PubMed: 36424481
DOI: 10.1038/s41580-022-00558-8 -
Molecular Cell Dec 2019Visualizing the location and dynamics of RNAs in live cells is key to understanding their function. Here, we identify two endonuclease-deficient, single-component...
Visualizing the location and dynamics of RNAs in live cells is key to understanding their function. Here, we identify two endonuclease-deficient, single-component programmable RNA-guided and RNA-targeting Cas13 RNases (dCas13s) that allow robust real-time imaging and tracking of RNAs in live cells, even when using single 20- to 27-nt-long guide RNAs. Compared to the aptamer-based MS2-MCP strategy, an optimized dCas13 system is user friendly, does not require genetic manipulation, and achieves comparable RNA-labeling efficiency. We demonstrate that the dCas13 system is capable of labeling NEAT1, SatIII, MUC4, and GCN4 RNAs and allows the study of paraspeckle-associated NEAT1 dynamics. Applying orthogonal dCas13 proteins or combining dCas13 and MS2-MCP allows dual-color imaging of RNAs in single cells. Further combination of dCas13 and dCas9 systems allows simultaneous visualization of genomic DNA and RNA transcripts in living cells.
Topics: CRISPR-Cas Systems; Cell Line, Tumor; Fluorescent Dyes; Humans; Molecular Imaging; Mucin-4; Protein Engineering; RNA; RNA, Guide, CRISPR-Cas Systems; RNA, Long Noncoding; Ribonucleases; Single Molecule Imaging; Staining and Labeling
PubMed: 31757757
DOI: 10.1016/j.molcel.2019.10.024 -
Cell Death and Differentiation Sep 2022Ferroptosis, a novel form of regulated cell death induced by iron-dependent lipid peroxidation, plays an essential role in the development and drug resistance of tumors....
Ferroptosis, a novel form of regulated cell death induced by iron-dependent lipid peroxidation, plays an essential role in the development and drug resistance of tumors. Long noncoding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported to be involved in the regulation of cell cycle, proliferation, apoptosis, and migration of tumor cells. However, the function and molecular mechanism of NEAT1 in regulating ferroptosis in tumors remain unclear. Here, we found that ferroptosis inducers erastin and RSL3 increased NEAT1 expression by promoting the binding of p53 to the NEAT1 promoter. Induced NEAT1 promoted the expression of MIOX by competitively binding to miR-362-3p. MIOX increased ROS production and decreased the intracellular levels of NADPH and GSH, resulting in enhanced erastin- and RSL3-induced ferroptosis. Importantly, overexpression of NEAT1 increased the anti-tumor activity of erastin and RSL3 by enhancing ferroptosis both in vitro and in vivo. Collectively, these data suggest that NEAT1 plays a novel and indispensable role in ferroptosis by regulating miR-362-3p and MIOX. Considering the clinical findings that HCC patients are insensitive to chemotherapy and immunotherapy, ferroptosis induction may be a promising therapeutic strategy for HCC patients with high NEAT1 expression.
Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Ferroptosis; Humans; Inositol Oxygenase; Liver Neoplasms; MicroRNAs; RNA, Long Noncoding
PubMed: 35338333
DOI: 10.1038/s41418-022-00970-9 -
Ageing Research Reviews Apr 2023Neurodegenerative diseases are the most common causes of disability worldwide. Given their high prevalence, devastating symptoms, and lack of definitive diagnostic... (Review)
Review
Neurodegenerative diseases are the most common causes of disability worldwide. Given their high prevalence, devastating symptoms, and lack of definitive diagnostic tests, there is an urgent need to identify potential biomarkers and new therapeutic targets. Long non-coding RNAs (lncRNAs) have recently emerged as powerful regulatory molecules in neurodegenerative diseases. Among them, lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported to be upregulated in Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). However, whether this is part of a protective or harmful mechanism is still unclear. This review summarizes our current knowledge of the role of NEAT1 in neurodegenerative diseases and its association with the characteristic aggregation of misfolded proteins: amyloid-β and tau in AD, α-synuclein in PD, mutant huntingtin in HD, and TAR DNA-binding protein-43 fused in sarcoma/translocated in liposarcoma in ALS. The aim of this review is to stimulate further research on more precise and effective treatments for neurodegenerative diseases.
Topics: Humans; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Huntington Disease; Neurodegenerative Diseases; Parkinson Disease; RNA, Long Noncoding
PubMed: 36738893
DOI: 10.1016/j.arr.2023.101878 -
American Journal of Cancer Research 2021Liquid-liquid phase separation (LLPS) has emerged as a mechanism that has been used to explain the formation of known organelles (e.g. nucleoli, promyelocytic leukemia... (Review)
Review
Liquid-liquid phase separation (LLPS) has emerged as a mechanism that has been used to explain the formation of known organelles (e.g. nucleoli, promyelocytic leukemia nuclear bodies (PML NBs), etc) as well as other membraneless condensates (e.g. nucleosome arrays, DNA damage foci, X-chromosome inactivation (XCI) center, paraspeckles, stress granules, proteasomes, autophagosomes, etc). The formation of membraneless condensates could be triggered by proteins containing modular domains or intrinsically disordered regions (IDRs) and nucleic acids. Multiple biological processes including transcription, chromatin organization, X-chromosome inactivation (XCI), DNA damage, tumorigenesis, autophagy, etc have been shown to utilize the principle of LLPS to facilitate these processes. This review will summarize the principle and components of LLPS, and describe how LLPS regulate these numerous biological processes and disruption of LLPS would cause disease formation. The role of LLPS in regulating normal cellular physiology and contributing to tumorigenesis will be discussed.
PubMed: 34522448
DOI: No ID Found -
Nature Chemical Biology Jan 2022An RNA-involved phase-separation model has been proposed for transcription control. However, the molecular links that connect RNA to the transcription machinery remain...
An RNA-involved phase-separation model has been proposed for transcription control. However, the molecular links that connect RNA to the transcription machinery remain missing. Here we find that RNA-binding proteins (RBPs) constitute half of the chromatin proteome in embryonic stem cells (ESCs), some being colocalized with RNA polymerase (Pol) II at promoters and enhancers. Biochemical analyses of representative RBPs show that the paraspeckle protein PSPC1 inhibits the RNA-induced premature release of Pol II, and makes use of RNA as multivalent molecules to enhance the formation of transcription condensates and subsequent phosphorylation and release of Pol II. This synergistic interplay enhances polymerase engagement and activity via the RNA-binding and phase-separation activities of PSPC1. In ESCs, auxin-induced acute degradation of PSPC1 leads to genome-wide defects in Pol II binding and nascent transcription. We propose that promoter-associated RNAs and their binding proteins synergize the phase separation of polymerase condensates to promote active transcription.
Topics: Gene Expression Regulation; Phosphorylation; Promoter Regions, Genetic; Protein Binding; RNA Polymerase II; RNA-Binding Proteins; Transcription, Genetic
PubMed: 34916619
DOI: 10.1038/s41589-021-00904-5 -
Cancer Research Dec 2021The dynamic changes of RNA N6-methyl-adenosine (mA) during cancer progression contribute to quick adaption to microenvironmental changes. Here, we profiled the cancer...
The dynamic changes of RNA N6-methyl-adenosine (mA) during cancer progression contribute to quick adaption to microenvironmental changes. Here, we profiled the cancer cell mA dynamics in the hypoxic tumor niche and its pathological consequences in glioblastoma multiforme (GBM). The mA demethylase ALKBH5 was induced in GBM models under hypoxic conditions and was associated with a hypoxic gene signature in GBM patient samples. Depletion or inactivation of ALKBH5 in GBM cells significantly suppressed hypoxia-induced tumor-associated macrophage (TAM) recruitment and immunosuppression in allograft tumors. Expression and secretion of CXCL8/IL8 were significantly suppressed in ALKBH5-deficient tumors. However, ALKBH5 did not regulate CXCL8 mA directly. Instead, hypoxia-induced ALKBH5 erased mA deposition from the lncRNA NEAT1, stabilizing the transcript and facilitating NEAT1-mediated paraspeckle assembly, which led to relocation of the transcriptional repressor SFPQ from the CXCL8 promoter to paraspeckles and, ultimately, upregulation of CXCL8/IL8 expression. Accordingly, ectopic expression of CXCL8 in ALKBH5-deficient GBM cells partially restored TAM recruitment and tumor progression. Together, this study links hypoxia-induced epitranscriptomic changes to the emergence of an immunosuppressive microenvironment facilitating tumor evasion. SIGNIFICANCE: Hypoxia induces tumor immune microenvironment remodeling through an ALKBH5-mediated epigenetic and epitranscriptomic mechanism, providing potential immunotherapeutic strategies for treating glioblastoma.
Topics: AlkB Homolog 5, RNA Demethylase; Animals; Apoptosis; Cell Proliferation; DNA Methylation; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Immunosuppressive Agents; Interleukin-8; Male; Mice; Mice, Inbred C57BL; Paraspeckles; Tumor Cells, Cultured; Tumor Microenvironment; Tumor-Associated Macrophages; Xenograft Model Antitumor Assays
PubMed: 34670781
DOI: 10.1158/0008-5472.CAN-21-1456 -
Theranostics 2022Hepatocellular Carcinoma (HCC) is a major form of liver cancer and a leading cause of cancer-related death worldwide. New insights into HCC pathobiology and mechanism...
Hepatocellular Carcinoma (HCC) is a major form of liver cancer and a leading cause of cancer-related death worldwide. New insights into HCC pathobiology and mechanism of drug actions are urgently needed to improve patient outcomes. HCC undergoes metabolic reprogramming of glucose metabolism from respiration to aerobic glycolysis, a phenomenon known as the 'Warburg Effect' that supports rapid cancer cell growth, survival, and invasion. mTOR is known to promote Warburg Effect, but the underlying mechanism(s) remains poorly defined. The aim of this study is to understand the mechanism(s) and significance of mTOR regulation of aerobic glycolysis in HCC. We profiled mTORC1-dependent long non-coding RNAs (lncRNAs) by RNA-seq of HCC cells treated with rapamycin. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were used to explore the transcriptional regulation of by mTORC1. [U-C]-glucose labeling and metabolomic analysis, extracellular acidification Rate (ECAR) by Seahorse XF Analyzer, and glucose uptake assay were used to investigate the role of mTOR-NEAT1-NONO signaling in the regulation of aerobic glycolysis. RNA immunoprecipitation (RIP) and NONO-binding motif scanning were performed to identify the regulatory mechanism of pre-mRNA splicing by mTOR-NEAT1. Myristoylated AKT1 (mAKT1)/NRAS-driven HCC model developed by hydrodynamic transfection (HDT) was employed to explore the significance of mTOR-NEAT1 signaling in HCC tumorigenesis and mTOR-targeted therapy. mTOR regulates lncRNA transcriptome in HCC and that NEAT1 is a major mTOR transcriptional target. Interestingly, although both NEAT1_1 and NEAT1_2 are down-regulated in HCC, only NEAT1_2 is significantly correlated with poor overall survival of HCC patients. NEAT1_2 is the organizer of nuclear paraspeckles that sequester the RNA-binding proteins NONO and SFPQ. We show that upon oncogenic activation, mTORC1 suppresses NEAT1_2 expression and paraspeckle biogenesis, liberating NONO/SFPQ, which in turn, binds to U5 within the spliceosome, stimulating mRNA splicing and expression of key glycolytic enzymes. This series of actions lead to enhanced glucose transport, aerobic glycolytic flux, lactate production, and HCC growth both and . Furthermore, the paraspeckle-mediated mechanism is important for the anticancer action of US FDA-approved drugs rapamycin/temsirolimus. These findings reveal a molecular mechanism by which mTOR promotes the 'Warburg Effect', which is important for the metabolism and development of HCC, and anticancer response of mTOR-targeted therapy.
Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Glucose; Glycolysis; Humans; Liver Neoplasms; Mechanistic Target of Rapamycin Complex 1; Paraspeckles; RNA, Long Noncoding; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 35547764
DOI: 10.7150/thno.72581 -
Essays in Biochemistry Dec 2020Paraspeckles are a type of subnuclear bodies built on the long noncoding RNA NEAT1 (nuclear paraspeckle assembly transcript 1, also known as MEN-ε/β or VINC-1).... (Review)
Review
Paraspeckles are a type of subnuclear bodies built on the long noncoding RNA NEAT1 (nuclear paraspeckle assembly transcript 1, also known as MEN-ε/β or VINC-1). Paraspeckles are involved in many physiological processes including cellular stress responses, cell differentiation, corpus luteum formation and cancer progression. Recently, ultra-resolution microscopy coupled with multicolor-labeling of paraspeckle components (the NEAT1 RNA and paraspeckle proteins) revealed the exquisite details of paraspeckle structure and function. NEAT1 transcripts are radially arranged to form a core-shell spheroidal structure, while paraspeckle proteins (PSPs) localize within different layers. Functional dissection of NEAT1 shows that the subdomains of NEAT1_2 are important for RNA stability, isoform switching and paraspeckle assembly via a liquid-liquid phase separation (LLPS) mechanism. We review recent progress on structure and organization of paraspeckles as well as how paraspeckles spatiotemporally control gene regulation through sequestration of diverse proteins and RNAs in cells.
Topics: Cell Nucleus; Gene Expression; Gene Expression Regulation; Humans; Protein Domains; Protein Isoforms; RNA Stability; RNA, Long Noncoding; RNA-Binding Proteins
PubMed: 32830222
DOI: 10.1042/EBC20200010