RESUMEN
N6 -Methyladenosine (m6 A) is an important RNA modification catalyzed by methyltransferase-like 3 (METTL3) and METTL14. m6 A homeostasis mediated by the methyltransferase (MTase) complex plays key roles in various biological processes. However, the mechanism underlying METTL14 protein stability and its role in m6 A homeostasis remain elusive. Here, we show that METTL14 stability is regulated by the competitive interaction of METTL3 with the E3 ligase STUB1. STUB1 directly interacts with METTL14 to mediate its ubiquitination at lysine residues K148, K156, and K162 for subsequent degradation, resulting in a significant decrease in total m6 A levels. The amino acid regions 450-454 and 464-480 of METTL3 are essential to promote METTL14 stabilization. Changes in STUB1 expression affect METTL14 protein levels, m6 A modification and tumorigenesis. Collectively, our findings uncover an ubiquitination mechanism controlling METTL14 protein levels to fine-tune m6 A homeostasis. Finally, we present evidence that modulating STUB1 expression to degrade METTL14 could represent a promising therapeutic strategy against cancer.
Asunto(s)
Adenosina , Metiltransferasas , Adenosina/metabolismo , Metiltransferasas/genética , HomeostasisRESUMEN
BACKGROUND: Glioma stem cells (GSCs) are responsible for glioma recurrence and drug resistance, yet the mechanisms underlying their maintenance remains unclear. This study aimed to identify enhancer-controlled genes involved in GSCs maintenance and elucidate the mechanisms underlying their regulation. METHODS: We analyzed RNA-seq data and H3K27ac ChIP-seq data from GSE119776 to identify differentially expressed genes and enhancers, respectively. Gene Ontology analysis was performed for functional enrichment. Transcription factors were predicted using the Toolkit for Cistrome Data Browser. Prognostic analysis and gene expression correlation was conducted using the Chinese Glioma Genome Atlas (CGGA) data. Two GSC cell lines, GSC-A172 and GSC-U138MG, were isolated from A172 and U138MG cell lines. qRT-PCR was used to detect gene transcription levels. ChIP-qPCR was used to detect H3K27ac of enhancers, and binding of E2F4 to target gene enhancers. Western blot was used to analyze protein levels of p-ATR and γH2AX. Sphere formation, limiting dilution and cell growth assays were used to analyze GSCs growth and self-renewal. RESULTS: We found that upregulated genes in GSCs were associated with ataxia-telangiectasia-mutated-and-Rad3-related kinase (ATR) pathway activation, and that seven enhancer-controlled genes related to ATR pathway activation (LIN9, MCM8, CEP72, POLA1, DBF4, NDE1, and CDKN2C) were identified. Expression of these genes corresponded to poor prognosis in glioma patients. E2F4 was identified as a transcription factor that regulates enhancer-controlled genes related to the ATR pathway activation, with MCM8 having the highest hazard ratio among genes positively correlated with E2F4 expression. E2F4 bound to MCM8 enhancers to promote its transcription. Overexpression of MCM8 partially restored the inhibition of GSCs self-renewal, cell growth, and the ATR pathway activation caused by E2F4 knockdown. CONCLUSION: Our study demonstrated that E2F4-mediated enhancer activation of MCM8 promotes the ATR pathway activation and GSCs characteristics. These findings offer promising targets for the development of new therapies for gliomas.
Asunto(s)
Glioma , Humanos , Glioma/genética , Glioma/metabolismo , Factores de Transcripción/metabolismo , Proliferación Celular/genética , Células Madre Neoplásicas/metabolismo , Proteínas de Mantenimiento de Minicromosoma/metabolismo , Factor de Transcripción E2F4/metabolismo , Proteínas Asociadas a Microtúbulos , Proteínas de la Ataxia Telangiectasia Mutada/metabolismoRESUMEN
Internal tandem duplication (ITD) mutations within FMS-like tyrosine kinase-3 (FLT3) occur in up to 30% of acute myeloid leukemia (AML) patients and confer a very poor prognosis. The oncogenic form of FLT3 is an important therapeutic target, and inhibitors specifically targeting FLT3 kinase can induce complete remission; however, relapse after remission has been observed due to acquired resistance with secondary mutations in FLT3, highlighting the need for new strategies to target FLT3-ITD mutations. Recent studies have reported that the aberrant formations of circular RNAs (circRNAs) are biological tumorigenesis-relevant mechanisms and potential therapeutic targets. Herein, we discovered a circRNA, circMYBL2, derived from the cell-cycle checkpoint gene MYBL2. circMYBL2 is more highly expressed in AML patients with FLT3-ITD mutations than in those without the FLT3-ITD mutation. We found that circMYBL2 knockdown specifically inhibits proliferation and promotes the differentiation of FLT3-ITD AML cells in vitro and in vivo. Interestingly, we found that circMYBL2 significantly influences the protein level of mutant FLT3 kinase, which contributes to the activation of FLT3-ITD-dependent signaling pathways. Mechanistically, circMYBL2 enhanced the translational efficiency of FLT3 kinase by increasing the binding of polypyrimidine tract-binding protein 1 (PTBP1) to FLT3 messenger RNA. Moreover, circMYBL2 knockdown impaired the cytoactivity of inhibitor-resistant FLT3-ITD+ cells, with a significant decrease in FLT3 kinase expression, followed by the inactivation of its downstream pathways. In summary, we are the first to reveal a circRNA that specifically influences FLT3-ITD AML and regulates FLT3 kinase levels through translational regulation, suggesting that circMYBL2 may be a potential therapeutic target for FLT3-ITD AML.
Asunto(s)
Proteínas de Ciclo Celular/genética , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Leucemia Mieloide Aguda/genética , Proteína de Unión al Tracto de Polipirimidina/metabolismo , ARN Circular/genética , Transactivadores/genética , Tirosina Quinasa 3 Similar a fms/genética , Animales , Línea Celular Tumoral , Progresión de la Enfermedad , Xenoinjertos , Humanos , Leucemia Mieloide Aguda/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Biosíntesis de Proteínas , Secuencias Repetidas en TándemRESUMEN
Herein, we report the discovery of a series of thieno[2,3-d]pyrimidin-4(3H)-one derivatives as a new class of ROCK inhibitors. Structure-activity relationship studies of these compounds led to the identification of the most potent compound, 3-(3-methoxybenzyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)thieno[2,3-d]pyrimidin-4(3H)-one (8k), which showed IC50 values of 0.004 µM and 0.001 µM against ROCK â and ROCK â ¡, respectively. In vitro, 8k significantly reduced the phosphorylation level of ROCK downstream signaling protein and induce changes in cell morphology and migration. Overall, this study provides a promising lead compound for drug discovery targeting ROCKs.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Pirimidinonas/química , Quinasas Asociadas a rho/antagonistas & inhibidores , Movimiento Celular/efectos de los fármacos , Descubrimiento de Drogas , Humanos , Fosforilación , Inhibidores de Proteínas Quinasas/metabolismo , Pirimidinonas/metabolismo , Relación Estructura-ActividadRESUMEN
OBJECTIVE: To study the moderated mediation for attention deficit/hyperactivity disorder (ADHD) with the symptoms of anxiety in children. METHODS: A total of 12â271 students were included with an average age of 8.9±1.9 years, including 6â743 male students and 5â508 female students, and 20 students with missing data on gender. Child psychological trauma questionnaires (parents version) and Conners questionnaires (parent version) were completed by the parents of primary school students. The data was studied by univariate analysis, multivariate analysis and moderated mediation analysis. RESULTS: The results of the univariate analysis showed that in all subjects, boys, and girls, the scores of hyperactivity index and childhood trauma were positively correlated with the score of anxiety (P<0.01), and ADHD and childhood trauma positively predicted anxiety disorder (P<0.001). The results of the multivariate analysis showed that in all subjects, boys, and girls, the scores of hyperactivity index (ADHD symptoms) and childhood trauma positively predicted the score of anxiety (P<0.001), and both ADHD and childhood trauma positively predicted anxiety disorder (P<0.001). The results of the moderated mediation analysis showed that childhood trauma was a mediating factor for the relationship between hyperactivity index and anxiety index in boys and girls (P<0.05), and sex moderated the relationship between hyperactivity index and anxiety index (P<0.001). CONCLUSIONS: ADHD symptoms/ADHD are closely associated with anxiety symptoms/anxiety disorder. Childhood trauma exerts a mediating effect on the relationship between ADHD symptoms and anxiety symptoms, and sex moderates the relationship between ADHD symptoms and anxiety symptoms.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Trastornos de la Conducta Infantil , Ansiedad , Trastornos de Ansiedad , Niño , Femenino , Humanos , Masculino , Encuestas y CuestionariosRESUMEN
The long noncoding RNA ANRIL has been found to be abnormally expressed and play important roles in different cancers. However, the expression and function of ANRIL in acute myeloid leukemia (AML) remain to be declared. In this study, we found that ANRIL is up-regulated in AML patients at diagnosis and down-regulated in patients after complete remission (CR). Functional studies showed that knockdown of ANRIL expression resulted in a decline in glucose uptake and inhibition of AML cell maintenance in vitro and in vivo. Mechanically, ANRIL was found to repress the expression of Adiponectin receptor (AdipoR1), a key regulator of glucose metabolism. Both ANRIL and AdipoR1 knockdown reduced the expression levels of phosphorylation of AMPK and SIRT1, implying a previously unappreciated ANRIL-AdipoR1-AMPK/SIRT1 signaling pathway in regulating cell glucose metabolism and survival in AML. The study is the first to demonstrate that ANRIL promotes malignant cell survival and cell glucose metabolism to accelerate AML progression and is a potential prognostic marker and therapeutic target in AML treatment.
Asunto(s)
Glucosa/metabolismo , Leucemia Mieloide Aguda/genética , Redes y Vías Metabólicas , ARN Largo no Codificante/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Receptores de Adiponectina/metabolismo , Sirtuina 1/genética , Regulación hacia ArribaRESUMEN
Immunoevasion is a hallmark of cancer progression, and immune checkpoint blockade has emerged as a promising strategy for cancer treatment. microRNAs (miRNAs) are important negative regulators of gene expression in the immune system. Here, we demonstrate that miR-708 regulates CD47, a transmembrane protein that inhibits phagocytosis in T cell acute lymphoblastic leukemia. miR-708 directly targeted CD47 through binding to 3'UTR and is inversely correlated with CD47 expression. Functional studies showed that restoration of miR-708 expression in the T-ALL cell line is sufficient to promote phagocytosis by macrophages in the absence or presence of the anti-CD47 antibody to eradicate T-ALL cells, and inhibited tumor engraftment in vivo. Together, our findings suggest that miR-708 is a key negative regulator of CD47 and may serve as an attractive candidate for immunotherapy of T-ALL.
Asunto(s)
Antígeno CD47/genética , Regulación Leucémica de la Expresión Génica , MicroARNs/genética , Fagocitosis/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Interferencia de ARN , Línea Celular Tumoral , Humanos , Fagocitosis/inmunología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/inmunologíaRESUMEN
Degradable resin- coated controlled release fertilizer is one of the hottest current research focuses in the field of fertilizer. In terms of practical application, the photodegradability characteristics of three kinds of coatings including polyethylene/hydrophilic nano-TiO2 composite, polyethylene/hydrophilic nano-TiO2 composite and pure polyethylene were analyzed under irradiation of sunlight and ultraviolet by ATR-FTIR, which was aimed to know their degradation behaviors under two conditions. The result showed that under irradiation of sunlight and ultraviolet, the type of functional group was not changed with the addition of the photo-catalyst, but the photo-catalyst just had an effect on intensity of functional groups. The trend was polyethylene/hydrophobic nano-TiO2 composite>polyethylene/hydrophilic nano-TiO2 composite>pure polyethylene. Furthermore, sunlight and ultraviolet had different effects on molecular structures of coatings. Under irradiation of sunlight, crosslinking reaction took place and ether bond was generated among the carbon chain of polyethylene except for the form of hydroperoxides. Then, carbon chain continued being oxidized to form carbonyl group. The existence of carbonyl group promoted the further degradation of coatings; under irradiation of ultraviolet, high local concentrations of reactive oxygen species were produced and the ability to attack the carbon chain of polymer was strong. Thus, the long alkyl chain of polyethylene was quickly oxidized to form intermediate products containing carbonyl groups. However, the irradiation experiment of ultraviolet didn't fully reveal the degradation behavior of coatings.
RESUMEN
BACKGROUND: Mixed-lineage leukemia (MLL) fusion gene caused by chromosomal rearrangement is a dominant oncogenic driver in leukemia. Due to having diverse MLL rearrangements and complex characteristics, MLL leukemia treated by currently available strategies is frequently associated with a poor outcome. Therefore, there is an urgent need to identify novel therapeutic targets for hematological malignancies with MLL rearrangements. METHODS: qRT-PCR, western blot, and spearman correction analysis were used to validate the regulation of LAMP5-AS1 on LAMP5 expression. In vitro and in vivo experiments were conducted to assess the functional relevance of LAMP5-AS1 in MLL leukemia cell survival. We utilized chromatin isolation by RNA purification (ChIRP) assay, RNA pull-down assay, chromatin immunoprecipitation (ChIP), RNA fluorescence in situ hybridization (FISH), and immunofluorescence to elucidate the relationship among LAMP5-AS1, DOT1L, and the LAMP5 locus. Autophagy regulation by LAMP5-AS1 was evaluated through LC3B puncta, autolysosome observation via transmission electron microscopy (TEM), and mRFP-GFP-LC3 puncta in autophagic flux. RESULTS: The study shows the crucial role of LAMP5-AS1 in promoting MLL leukemia cell survival. LAMP5-AS1 acts as a novel autophagic suppressor, safeguarding MLL fusion proteins from autophagic degradation. Knocking down LAMP5-AS1 significantly induced apoptosis in MLL leukemia cell lines and primary cells and extended the survival of mice in vivo. Mechanistically, LAMP5-AS1 recruits the H3K79 histone methyltransferase DOT1L to LAMP5 locus, directly activating LAMP5 expression. Importantly, blockade of LAMP5-AS1-LAMP5 axis can represses MLL fusion proteins by enhancing their degradation. CONCLUSIONS: The findings underscore the significance of LAMP5-AS1 in MLL leukemia progression through the regulation of the autophagy pathway. Additionally, this study unveils the novel lncRNA-DOT1L-LAMP5 axis as promising therapeutic targets for degrading MLL fusion proteins.
RESUMEN
Background: Following carotid artery stenting (CAS), new ipsilateral ischemic lesions (NIILs) in the brain are frequently seen using diffusion-weighted imaging (DWI). This study's goal was to identify the imaging characteristics associated with NIILs after CAS by high-resolution magnetic resonance vessel wall imaging (HR-VWI). Methods: This was a case-control study. 109 patients who received CAS for atherosclerotic carotid stenosis were retrospectively collected and categorized into NIILs positive and NIILs negative groups. Based on the existence or absence of stroke symptoms after CAS, the NIILs positive group was split into two subgroups: the NIILs symptomatic group and the NIILs asymptomatic group. Patients underwent preoperative HR-VWI and brain magnetic resonance imaging (MRI) within 7 days preoperatively and within 3 days postoperatively. Quantitatively assess carotid plaque burden and components using HR-VWI. The baseline and HR-VWI imaging characteristics of all patients were retrospectively analyzed. To ascertain the imaging characteristics connected with NIILs after CAS, logistic regression analysis was carried out. Results: Among 109 patients, 38 patients (34.9%) developed NIILs after CAS. Six patients (5.5%) developed symptomatic stroke with NIILs. The logistic regression analysis revealed that maximum wall thickness (Max WT) [odds ratio (OR), 1.53; 95% confidence interval (CI): 1.20-1.96; P=0.001], the maximum area percentage of lipid-rich necrotic core (LRNC) (OR, 1.05; 95% CI: 1.03-1.07; P<0.001), the volume of LRNC (OR, 1.004; 95% CI: 1.002-1.005; P<0.001), the maximum area percentage of intraplaque hemorrhage (IPH) (OR, 1.17; 95% CI: 1.11-1.24; P<0.001), the volume of IPH (OR, 1.06; 95% CI: 1.03-1.08; P<0.001), and maximum circumference score of calcification in a single slice (OR, 1.66; 95% CI: 1.04-2.63; P=0.03) were linked with NIILs following CAS. Conclusions: The massive IPH, LRNC, and heavy circumferential calcification were associated with NIILs after CAS. Preoperative quantitative assessment of carotid plaque using HR-VWI may be useful for predicting NIILs following CAS.
RESUMEN
Inflammation is an innate immune response to infection, and it is the main factor causing bodily injury and other complications in the pathological process. Ginsenoside Rh4 (G-Rh4), a minor ginsenoside of Panax ginseng C. A. Meyer and Panax notoginseng, has excellent pharmacological properties. However, many of its major pharmacological mechanisms, including anti-inflammatory actions, remain unrevealed. In this study, network pharmacology and an experimental approach were employed to elucidate the drug target and pathways of G-Rh4 in treating inflammation. The potential targets of G-Rh4 were selected from the multi-source databases, and 58 overlapping gene symbols related to G-Rh4 and inflammation were obtained for generating a protein-protein interaction (PPI) network. Molecular docking revealed the high affinities between key proteins and G-Rh4. Gene ontology (GO) and pathway enrichment analyses were used to analyze the screened core targets and explore the target-pathway networks. It was found that the JAK-STAT signaling pathway, TNF signaling pathway, NF-κB signaling pathway, and PI3K-Akt signaling pathway may be the key and main pathways of G-Rh4 to treat inflammation. Additionally, the potential molecular mechanisms of G-Rh4 predicted from network pharmacology analysis were validated in RAW264.7 cells. RT-PCR, Western blot, and ELISA analysis indicated that G-Rh4 significantly inhibited the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1ß, as well as inflammation-related enzymes in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Moreover, in vitro experiments evaluated that Ginsenoside Rh4 exerts anti-inflammatory effects via the NF-κB and STAT3 signaling pathways. It is believed that our study will provide the basic scientific evidence that G-Rh4 has potential anti-inflammatory effects for further clinical studies.
RESUMEN
Long noncoding RNAs (lncRNAs) are usually 5' capped and 3' polyadenylated, similar to most typical mRNAs. However, recent studies revealed a type of snoRNA-related lncRNA with unique structures, leading to questions on how they are processed and how they work. Here, we identify a novel snoRNA-related lncRNA named LNC-SNO49AB containing two C/D box snoRNA sequences, SNORD49A and SNORD49B; and show that LNC-SNO49AB represents an unreported type of lncRNA with a 5'-end m7G and a 3'-end snoRNA structure. LNC-SNO49AB was found highly expressed in leukemia patient samples, and silencing LNC-SNO49AB dramatically suppressed leukemia progression in vitro and in vivo. Subcellular location indicated that the LNC-SNO49AB is mainly located in nucleolus and interacted with the nucleolar protein fibrillarin. However, we found that LNC-SNO49AB does not play a role in 2'-O-methylation regulation, a classical function of snoRNA; instead, its snoRNA structure affected the lncRNA stability. We further demonstrated that LNC-SNO49AB could directly bind to the adenosine deaminase acting on RNA 1(ADAR1) and promoted its homodimerization followed by a high RNA A-to-I editing activity. Transcriptome profiling shows that LNC-SNO49AB and ADAR1 knockdown respectively share very similar patterns of RNA modification change in downstream signaling pathways, especially in cell cycle pathways. These findings suggest a previously unknown class of snoRNA-related lncRNAs, which function via a manner in nucleolus independently on snoRNA-guide rRNA modification. This is the first report that a lncRNA regulates genome-wide RNA A-to-I editing by enhancing ADAR1 dimerization to facilitate hematopoietic malignancy, suggesting that LNC-SNO49AB may be a novel target in therapy directed to leukemia.
RESUMEN
Small nucleolar RNAs (snoRNAs) are commonly acknowledged as a class of homogeneous non-coding RNAs that guide ribosomal RNA modifications. However, snoRNAs referred to as orphans have largely unknown functions. Here, we systematically profile chromatin-associated snoRNAs (casnoRNAs) in mammalian cells and identify a subgroup of orphan casnoRNAs responding to DNA damage stress, among which SNORA73 shows the most marked reduction in chromatin enrichment. Downregulated SNORA73 maintains cancer genome stability and differentiation block in hematopoietic malignancy. Mechanistically, casnoRNA the 5' end non-canonical structure of SNORA73 is critical for its function and binding to poly (ADP-ribose) polymerase 1 (PARP1). SNORA73 inhibits PARP1 auto-PARylation to affect cancer genome stability by forming a small nucleolar ribonucleoprotein (snoRNP) with PARP1 and canonical H/ACA proteins DKC1/NHP2. Our findings reveal the role of an orphan snoRNA serving as casnoRNA and highlights a link between non-canonical structure of snoRNA and their functional diversity.
Asunto(s)
Cromatina , ARN Nucleolar Pequeño , Animales , Proteínas de Ciclo Celular/metabolismo , Diferenciación Celular/genética , Cromatina/genética , Daño del ADN/genética , ARN Nucleolar Pequeño/genética , ARN Nucleolar Pequeño/metabolismo , Ribonucleoproteínas Nucleolares Pequeñas/genéticaRESUMEN
Jian-Gan-Xiao-Zhi decoction (JGXZ) has demonstrated beneï¬cial eï¬ects on nonalcoholic fatty liver disease (NAFLD). However, the mechanisms by which JGXZ improve NAFLD are still unclear. Methods. In this study, we first used a high-fat diet (HFD) to establish a NAFLD rat model to clarify the therapeutic effect of JGXZ on NAFLD. Secondly, we used network pharmacology to predict the potential targets of JGXZ on NAFLD, and then the key targets obtained from network pharmacology were verified. Finally, we used untargeted metabolomics to study the metabolic regulatory mechanism of JGXZ. Results. JGXZ treatment could decrease body weight and ameliorate dyslipidemia in NAFLD model rats. H&E and oil red O staining indicated that JGXZ reduced steatosis and inï¬ltration of inï¬ammatory cells in the liver. In addition, network pharmacology research found that the potential targets of JGXZ on NAFLD pathway were mainly associated with improving oxidative stress, apoptosis, inflammation, lipid metabolism disorders, and insulin resistance. Further experimental verification confirmed that JGXZ could inhibit inflammation and improve oxidative stress, insulin resistance, and lipid metabolism disorders. Serum untargeted metabolomics analyses indicated that the JGXZ in the treatment of NAFLD may work through the linoleic acid metabolism, alpha-linolenic acid metabolism, tryptophan metabolism, and glycerophospholipid metabolism pathways. Conclusions. In conclusion, this study found that JGXZ has an ameliorative effect on NAFLD, and JGXZ alleviates the inflammatory response and oxidative stress and lipid metabolism disorders in NAFLD rats. The mechanism of action of JGXZ in the treatment of NAFLD may be related to the regulation of linoleic acid metabolism, tryptophan metabolism, alpha-linolenic acid metabolism, and glycerophospholipid metabolism.
RESUMEN
Recent studies have reported that circular RNAs (circRNAs) are a newly discovered type of ubiquitous, abundant and stable noncoding RNAs (ncRNAs) that play important roles in various biological processes in eukaryotic organisms. However, the biological functions of circRNAs in plants remain largely unknown and need further studies. Identification of plant circRNAs from plant circRNA database or sequencing analysis is a first step to investigate their functions. Here, we provide a series of protocols for circRNA identification including circular forms, composition features and location even in plant tissues which are rich in polysaccharides and polyphenols and difficult to extract RNAs.
Asunto(s)
ARN Circular/genética , ARN/genéticaRESUMEN
Lack of clarity of the mechanisms that underlie leukemogenesis obstructs the diagnosis, prognosis, and treatment of leukemia. Research has found that small nuclear RNA (snoRNA) plays an essential role in leukemia. These small non-coding RNAs are involved in ribosome biogenesis, including the 2'-O-methylation and pseudouridylation of precursor ribosomal RNA (pre-rRNA), and pre-rRNA splicing. Recently, many snoRNAs were found to be orphans that have no predictable RNA modification targets, but these RNAs have always been found to be located in different subcellular organelles, and they play diverse roles. Using high-throughput technology, snoRNA expression profiles have been revealed in leukemia, and some of the deregulated snoRNAs may regulate the cell cycle, differentiation, proliferation, and apoptosis in leukemic cells and confer drug resistance during leukemia treatment. In this review, we discuss the expression profiles and functions of snoRNAs, particularly orphan snoRNAs, in leukemia. It is possible that the dysregulated snoRNAs are promising diagnosis and prognosis markers for leukemia, which may serve as potential therapeutic targets in leukemia treatment.
RESUMEN
The cereal endosperm is a major factor determining seed size and shape. However, the molecular mechanisms of endosperm development are not fully understood. Long noncoding RNAs (lncRNAs) function in various biological processes. Here we show a lncRNA, MISSEN, that plays an essential role in early endosperm development in rice (Oryza sativa). MISSEN is a parent-of-origin lncRNA expressed in endosperm, and negatively regulates endosperm development, leading to a prominent dent and bulge in the seed. Mechanistically, MISSEN functions through hijacking a helicase family protein (HeFP) to regulate tubulin function during endosperm nucleus division and endosperm cellularization, resulting in abnormal cytoskeletal polymerization. Finally, we revealed that the expression of MISSEN is inhibited by histone H3 lysine 27 trimethylation (H3K27me3) modification after pollination. Therefore, MISSEN is the first lncRNA identified as a regulator in endosperm development, highlighting the potential applications in rice breeding.
Asunto(s)
Oryza/metabolismo , ARN Largo no Codificante/metabolismo , ARN de Planta/metabolismo , Semillas/metabolismo , Regulación de la Expresión Génica de las Plantas , Oryza/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , ARN Largo no Codificante/genética , ARN de Planta/genética , Semillas/genéticaRESUMEN
Noncoding RNAs (ncRNAs) are a large segment of the transcriptome that do not have apparent protein-coding roles, but they have been verified to play important roles in diverse biological processes, including disease pathogenesis. With the development of innovative technologies, an increasing number of novel ncRNAs have been uncovered; information about their prominent tissue-specific expression patterns, various interaction networks, and subcellular locations will undoubtedly enhance our understanding of their potential functions. Here, we summarized the principles and innovative methods for identifications of novel ncRNAs that have potential functional roles in cancer biology. Moreover, this review also provides alternative ncRNA databases based on high-throughput sequencing or experimental validation, and it briefly describes the current strategy for the clinical translation of cancer-associated ncRNAs to be used in diagnosis.
Asunto(s)
ARN no Traducido/fisiología , Cromatina/genética , Bases de Datos Genéticas , Regulación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Análisis por Micromatrices , Modelos Genéticos , Neoplasias/genética , Neoplasias/metabolismo , Sistemas de Lectura Abierta/genética , Especificidad de Órganos , Biosíntesis de Proteínas , ARN Neoplásico/genética , ARN Neoplásico/fisiología , ARN no Traducido/clasificación , ARN no Traducido/genética , ARN no Traducido/aislamiento & purificación , RNA-Seq , Ribosomas/metabolismo , Análisis de la Célula Individual , Fracciones Subcelulares/química , Transcripción GenéticaRESUMEN
The poor dispersity and oxidation resistance of ferromagnetic metal nanoparticles can induce serious deterioration in electromagnetic properties, which then significantly limits the application of this catalog of materials. In this work, sandwich-like Co/rGo/Co composites were in situ constructed, in which monodispersed Co nanoparticles with diameters of 20-60â¯nm were densely dispersed on both sides of rGO nanosheets. A connecting network between the densely-packed Co nanoparticles can be formed, where Co nanoparticles are abutted or bridged to each other through a neck of Co. These sandwich-like composites evidently contributed to improved permittivity and permeability, which was ascribed to the enhanced interface polarization and exchange coupling in this Co nanoparticles densely-packed structure. A maximum reflection loss (RLmax) of -61â¯dB (at 11.1â¯GHz) together with an efficient absorbing bandwidth (RLâ¯<â¯-10â¯dB, ERL10) of 4â¯GHz was obtained at a very thin matching thickness of 2â¯mm. The coating also presented a potential double-band absorbing performance, at SC band and Ku band, respectively. The excellent electromagnetic absorbing performances were ascribed to the synergistic effect of multiple dielectric losses and ferromagnetic losses. The sandwich-like Co/rGO/Co composites proposed an alternative way for broadband and high-efficiency absorption and provided a typical structure to analyze the loss mechanisms.
RESUMEN
BACKGROUND: Long noncoding enhancer RNAs (lnc-eRNAs) are a subset of stable eRNAs identified from annotated lncRNAs. They might act as enhancer activity-related therapeutic targets in cancer. However, the underlying mechanism of epigenetic activation and their function in cancer initiation and progression remain largely unknown. RESULTS: We identify a set of lncRNAs as lnc-eRNAs according to the epigenetic signatures of enhancers. We show that these lnc-eRNAs are broadly activated in MLL-rearranged leukemia (MLL leukemia), an aggressive leukemia caused by a chromosomal translocation, through a mechanism by which the HOXA cluster initiates enhancer activity, and the epigenetic reader BRD4 cooperates with the coregulator MLL fusion oncoprotein to induce transcriptional activation. To demonstrate the functional roles of lnc-eRNAs, two newly identified lnc-eRNAs transcribed from the SEELA eRNA cluster (SEELA), SEELA1 and SEELA2, are chosen for further studies. The results show that SEELA mediated cis-activated transcription of the nearby oncogene Serine incorporate 2 (SERINC2) by directly binding to the K31 amino acid (aa) of histone H4. Chromatin-bound SEELA strengthens the interaction between chromatin and histone modifiers to promote histone recognition and oncogene transcription. Further studies show that the SEELA-SERINC2 axis regulated aspects of cancer metabolism, such as sphingolipid synthesis, to affect leukemia progression. CONCLUSIONS: This study shows that lnc-eRNAs are epigenetically activated by cancer-initiating oncoproteins and uncovers a cis-activating mechanism of oncogene transcription control based on lnc-eRNA-mediated epigenetic regulation of enhancer activity, providing insights into the critical roles of lnc-eRNAs in cancer initiation and progression.