miR-137 confers robustness to the territorial restriction of the neural plate border.

The neural plate border (NPB) of vertebrate embryos is segregated from the neural plate (NP) and epidermal regions, and comprises an intermingled group of progenitors with multiple fate potential. Recent studies have shown that, during the gastrula stage, TFAP2A acts as a pioneer factor in remodeling the epigenetic landscape required to activate components of the NPB induction program. Here, we show that chick Tfap2a has two highly conserved binding sites for miR-137, and both display a reciprocal expression pattern at the NPB and NP, respectively. In addition, ectopic miR-137 expression reduced TFAP2A, whereas its functional inhibition expanded their territorial distribution overlapping with PAX7. Furthermore, we demonstrate that loss of the de novo DNA methyltransferase DNMT3A expanded miR-137 expression to the NPB. Bisulfite sequencing revealed a markedly elevated presence of non-canonical CpH methylation within the miR-137 promoter region when comparing NPB and NP samples. Our findings show that miR-137 contributes to the robustness of NPB territorial restriction in vertebrate development.

miR-137 regulates PTP61F, affecting insulin signaling, metabolic homeostasis, and starvation resistance in Drosophila.

miR-137 is a highly conserved brain-enriched microRNA (miRNA) that has been associated with neuronal function and proliferation. Here, we show that Drosophila miR-137 null mutants display increased body weight with enhanced triglyceride content and decreased locomotor activity. In addition, when challenged by nutrient deprivation, miR-137 mutants exhibit reduced motivation to feed and prolonged survival. We show through genetic epistasis and rescue experiments that this starvation resistance is due to a disruption in insulin signaling. Our studies further show that miR-137 null mutants exhibit a drastic reduction in levels of the phosphorylated/activated insulin receptor, InR (InR-P). We investigated if this is due to the predicted miR-137 target, Protein Tyrosine Phosphatase 61F (PTP61F), ortholog of mammalian TC-PTP/PTP1B, which are known to dephosphorylate InR-P. Indeed, levels of an endogenously tagged GFP-PTP61F are significantly elevated in miR-137 null mutants, and we show that overexpression of PTP61F alone is sufficient to mimic many of the metabolic phenotypes of miR-137 mutants. Finally, we knocked-down elevated levels of PTP61F in the miR-137 null mutant background and show that this rescues levels of InR-P, restores normal body weight and triglyceride content, starvation sensitivity, as well as attenuates locomotor and starvation-induced feeding defects. Our study supports a model in which miR-137 is critical for dampening levels of PTP61F, thereby maintaining normal insulin signaling and energy homeostasis.

The evolutionarily conserved miRNA-137 targets the neuropeptide hypocretin/orexin and modulates the wake to sleep ratio.

Hypocretin (Hcrt), also known as orexin, neuropeptide signaling stabilizes sleep and wakefulness in all vertebrates. A lack of Hcrt causes the sleep disorder narcolepsy, and increased Hcrt signaling has been speculated to cause insomnia, but while the signaling pathways of Hcrt are relatively well-described, the intracellular mechanisms that regulate its expression remain unclear. Here, we tested the role of microRNAs (miRNAs) in regulating Hcrt expression. We found that miR-137, miR-637, and miR-654-5p target the human HCRT gene. miR-137 is evolutionarily conserved and also targets mouse Hcrt as does miR-665. Inhibition of miR-137 specifically in Hcrt neurons resulted in Hcrt upregulation, longer episodes of wakefulness, and significantly longer wake bouts in the first 4 h of the active phase. IL-13 stimulation upregulated endogenous miR-137, while Hcrt mRNA decreased both in vitro and in vivo. Furthermore, knockdown of miR-137 in zebrafish substantially increased wakefulness. Finally, we show that in humans, the MIR137 locus is genetically associated with sleep duration. In conclusion, these results show that an evolutionarily conserved miR-137:Hcrt interaction is involved in sleep­wake regulation.

TNF inhibits AQP2 expression via a miR137-dependent pathway.

As miR-137 is a regulator of aquaporin (AQP)2 expression and tumor necrosis factor (TNF) inhibits the expression of several extrarenal AQPs, we tested the hypothesis that TNF inhibits AQP2 in the kidney via a miR-137-dependent mechanism. AQP2 mRNA and protein expression decreased ∼70% and 53%, respectively, in primary renal inner medullary collecting duct (IMCD) cells transfected with a miRNA mimic of mmu-miR-137, suggesting that miR-137 directly targets AQP2 mRNA in these cells. Exposure of IMCD cells for 2 h to 400 mosmol/kgH2O medium increased mmu-miR-137 mRNA expression about twofold, conditions that also increased TNF production approximately fourfold. To determine if the increase in mmu-miR-137 mRNA expression was related to the concomitant increase in TNF, IMCD cells were transfected with a lentivirus construct to silence TNF. This construct decreased mmu-miR-137 mRNA expression by ∼63%, suggesting that TNF upregulates the expression of miR-137. Levels of miR-137 also increased approximately twofold in IMCD tubules isolated from male mice given 1% NaCl in the drinking water for 3 days. Intrarenal lentivirus silencing of TNF increased AQP2 mRNA levels and protein expression concomitant with a decrease in miR-137 levels in tubules isolated from mice given NaCl. The changes in AQP2 expression levels affected the diluting ability of the kidney, which was assessed by measuring urine osmolality and urine volume, as the decrease in these parameters after renal silencing of TNF was prevented on intrarenal administration of miR-137. The study reveals a novel TNF function via a miR-137-dependent mechanism that regulates AQP2 expression and function.NEW & NOTEWORTHY An emerging intratubular tumor necrosis factor system, functioning during normotensive noninflammatory conditions, acts as a breaking mechanism that attenuates both the increases in Na+-K+-2Cl- cotransporter and aquaporin-2 induced by arginine vasopressin, thereby contributing to the regulation of electrolyte balance and blood pressure. A greater appreciation for the role of cytokines as mediators of immunophysiological responses may help reveal the relationship between the immune system and other physiological systems.

RhoGDIß inhibition via miR-200c/AUF1/SOX2/miR-137 axis contributed to lncRNA MEG3 downregulation-mediated malignant transformation of human bronchial epithelial cells.

Nickel pollution is a recognized factor contributing to lung cancer. Understanding the molecular mechanisms of its carcinogenic effects is crucial for lung cancer prevention and treatment. Our previous research identified the downregulation of a long noncoding RNA, maternally expressed gene 3 (MEG3), as a key factor in transforming human bronchial epithelial cells (HBECs) into malignant cells following nickel exposure. In our study, we found that deletion of MEG3 also reduced the expression of RhoGDIß. Notably, artificially increasing RhoGDIß levels counteracted the malignant transformation caused by MEG3 deletion in HBECs. This indicates that the reduction in RhoGDIß contributes to the transformation of HBECs due to MEG3 deletion. Further exploration revealed that MEG3 downregulation led to enhanced c-Jun activity, which in turn promoted miR-200c transcription. High levels of miR-200c subsequently increased the translation of AUF1 protein, stabilizing SOX2 messenger RNA (mRNA). This stabilization affected the regulation of miR-137, SP-1 protein translation, and the suppression of RhoGDIß mRNA transcription and protein expression, leading to cell transformation. Our study underscores the co-regulation of RhoGDIß expression by long noncoding RNA MEG3, multiple microRNAs (miR-200c and miR-137), and RNA-regulated transcription factors (c-Jun, SOX2, and SP1). This intricate network of molecular events sheds light on the nature of lung tumorigenesis. These novel findings pave the way for developing targeted strategies for the prevention and treatment of human lung cancer based on the MEG3/RhoGDIß pathway.

Synergistic effect of mesenchymal stem cell-derived extracellular vesicle and miR-137 alleviates autism-like behaviors by modulating the NF-κB pathway.

Autism spectrum disorder (ASD) is a multifaceted neurodevelopmental disorder predominant in childhood. Despite existing treatments, the benefits are still limited. This study explored the effectiveness of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) loaded with miR-137 in enhancing autism-like behaviors and mitigating neuroinflammation. Utilizing BTBR mice as an autism model, the study demonstrated that intranasal administration of MSC-miR137-EVs ameliorates autism-like behaviors and inhibits pro-inflammatory factors via the TLR4/NF-κB pathway. In vitro evaluation of LPS-activated BV2 cells revealed that MSC-miR137-EVs target the TLR4/NF-κB pathway through miR-137 inhibits proinflammatory M1 microglia. Moreover, bioinformatics analysis identified that MSC-EVs are rich in miR-146a-5p, which targets the TRAF6/NF-κB signaling pathway. In summary, the findings suggest that the integration of MSC-EVs with miR-137 may be a promising therapeutic strategy for ASD, which is worthy of clinical adoption.

The Role of miR-137 in Neurodegenerative Disorders.

Neurodegenerative diseases affect an increasing part of the population of modern societies, burdening healthcare systems and causing immense suffering at the personal level. The pathogenesis of several of these disorders involves dysregulation of gene expression, which depends on several molecular processes ranging from transcription to protein stability. microRNAs (miRNAs) are short non-coding RNA molecules that modulate gene expression by suppressing the translation of partially complementary mRNAs. miR-137 is a conserved, neuronally enriched miRNA that is implicated in neurodegeneration. Here, we review the current body of knowledge about the role that miR-137 plays in five prominent neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The presented data indicate that, rather than having a general neuroprotective role, miR-137 modulates the pathology of distinct disorders differently.

CircRNA3616 knockdown attenuates inflammation and apoptosis in spinal cord injury by inhibiting TLR4/NF-κB activity via sponging miR-137.

PURPOSE: The present work focused on exploring the role of circRNA3616 in neuronal inflammation and apoptosis in spinal cord injury (SCI). METHODS: The SCI mouse model and circRNA3616 knockdown SCI mouse model were established. This work focused on assessing the mouse locomotor function using Basso Mouse Scale (BMS) and BMS subscore. Hematoxylin-eosin (HE) staining and Tunel staining were conducted, while myeloperoxidase (MPO) activity was also detected on spinal cord tissues. We also knocked down circRNA3616 expression in NSC-34 cells. Meanwhile, the SCI cell model was established by oxygen glucose deprivation (OGD) in NSC-34 cells. Moreover, we conducted dual-luciferase reporter gene assay. Flow cytometry (FCM) was conducted to detect SCI cell apoptosis, whereas cell counting kit-8 (CCK-8) assay was performed to analyze cell viability. This study also implemented enzyme-linked immunosorbent assay to detect inflammatory factors in spinal cord tissues, serum, and cells. RESULTS: CircRNA3616 knockdown reduced the damage, inflammatory response, apoptosis, and MPO activity in SCI mouse serum and spinal cord tissues. CircRNA3616 knockdown increased BMS and BMS subscore of SCI mice. CircRNA3616 up-regulated TLR4 expression by sponging miR-137. CircRNA3616 knockdown inhibited the TLR4, p-IkBα, p-p65/p65 protein expression, while promoting IkBα protein expression within SCI mouse spinal cord. TLR4 reversed circRNA3616 knockdown-induced inhibition on NF-κB pathway activity in SCI cells. CircRNA3616 knockdown attenuated neuronal cell inflammation and apoptosis via TLR4/NF-κB pathway after SCI. CONCLUSION: CircRNA3616 silencing attenuates inflammation and apoptosis in SCI by inhibiting TLR4/NF-κB activity via sponging miR-137. CircRNA3616 is the possible anti-SCI therapeutic target.

Quercetin suppresses retinoblastoma cell proliferation and invasion and facilitates oxidative stress-induced apoptosis through the miR-137/FNDC5 axis.

Retinoblastoma (RB) constitutes a prevalent malignancy in clinic and usually occurs in children under the age of 5 years old. The increased frequency of malignant tumor metastases and the delayed diagnosis and treatment caused unsatisfactory therapeutic efficiency. Quercetin was formerly identified to impede tumor growth in certain malignancies. Our study attempted to investigate the effects and mechanisms of quercetin in Rb development, in order to provide an effective clinical therapeutic approach. Rb cell lines (WER1-RB1 and Y79) were incubated with different concentrations of quercetin, and then cell proliferation, invasion, apoptosis, and oxidative stress were determined. It was showed that quercetin restrained Rb cell proliferation and invasion, and induced cell apoptosis and oxidative stress in a dose dependent manner. Moreover, we found that quercetin incubation upregulated miR-137 expression in Rb cells. MiR-137 inhibition abrogated quercetin-mediated inhibition of Rb cell progression. Furthermore, dual-luciferase reporter gene assay validated that fibronectin type III domain-containing protein 5 (FNDC5) was a target for miR-137. MiR-137 overexpression restrained proliferation and invasion, and enhanced apoptosis and oxidative stress in Rb cells, whereas FNDC5 overexpression abrogated these effects. Additionally, nude mice were injected with WER1-RB1 cells to establish a xenograft tumor model, and then treated with 50 or 100 mg/kg quercetin. Quercetin treatment mitigated xenograft tumor growth in nude mice. In conclusion, quercetin restrained proliferation and invasion, and induced apoptosis and oxidative stress in Rb cells through regulating the miR-137/FNDC5 pathway. We expected that our study could provide an effective approach for Rb treatment. However, quercetin and miR-137 may have off-target effects in Rb cells, and our study still has certain limitations. Therefore, we will investigate the effects of quercetin on other signaling pathways in Rb cells and explore the application of combination therapy in follow-up experiments, in order to provide a rigorous research basis for the treatment of Rb with quercetin.

Early-Stage Application of Agomir-137 Promotes Locomotor Recovery in a Mouse Model of Motor Cortex Injury.

Traumatic brain injury (TBI) is a significant risk factor for neurodegenerative disorders, and patients often experience varying degrees of motor impairment. MiR-137, a broadly conserved and brain-enriched miRNA, is a key regulator in neural development and in various neurological diseases. Following TBI, the expression of miR-137 is dramatically downregulated. However, whether miR-137 is a therapeutic target for TBI still remains unknown. Here, for the first time, we demonstrate that intranasal administration of miR-137 agomir (a mimic) in the early stage (0-7 days) of TBI effectively inhibits glial scar formation and improves neuronal survival, while early-stage administration of miR-137 antagomir (an inhibitor) deteriorates motor impairment. This study elucidates the therapeutic potential of miR-137 mimics in improving locomotor recovery following motor cortex injury.

Integrated Bioinformatics Analysis Confirms the Diagnostic Value of Nourin-Dependent miR-137 and miR-106b in Unstable Angina Patients.

The challenge of rapidly diagnosing myocardial ischemia in unstable angina (UA) patients presenting to the Emergency Department (ED) is due to a lack of sensitive blood biomarkers. This has prompted an investigation into microRNAs (miRNAs) related to cardiac-derived Nourin for potential diagnostic application. The Nourin protein is rapidly expressed in patients with acute coronary syndrome (ACS) (UA and acute myocardial infarction (AMI)). MicroRNAs regulate gene expression through mRNA binding and, thus, may represent potential biomarkers. We initially identified miR-137 and miR-106b and conducted a clinical validation, which demonstrated that they were highly upregulated in ACS patients, but not in healthy subjects and non-ACS controls. Using integrated comprehensive bioinformatics analysis, the present study confirms that the Nourin protein targets miR-137 and miR-106b, which are linked to myocardial ischemia and inflammation associated with ACS. Molecular docking demonstrated robust interactions between the Nourin protein and miR137/hsa-miR-106b, involving hydrogen bonds and hydrophobic interactions, with -10 kcal/mol binding energy. I-TASSER generated Nourin analogs, with the top 10 chosen for structural insights. Antigenic regions and MHCII epitopes within the Nourin SPGADGNGGEAMPGG sequence showed strong binding to HLA-DR/DQ alleles. The Cytoscape network revealed interactions of -miR137/hsa-miR--106b and Phosphatase and tensin homolog (PTEN) in myocardial ischemia. RNA Composer predicted the secondary structure of miR-106b. Schrödinger software identified key Nourin-RNA interactions critical for complex stability. The study identifies miR-137 and miR-106b as potential ACS diagnostic and therapeutic targets. This research underscores the potential of miRNAs targeting Nourin for precision ACS intervention. The analysis leverages RNA Composer, Schrödinger, and I-TASSER tools to explore interactions and structural insights. Robust Nourin-miRNA interactions are established, bolstering the case for miRNA-based interventions in ischemic injury. In conclusion, the study contributes to UA and AMI diagnosis strategies through bioinformatics-guided exploration of Nourin-targeting miRNAs. Supported by comprehensive molecular analysis, the hypoxia-induced miR-137 for cell apoptosis (a marker of cell damage) and the inflammation-induced miR-106b (a marker of inflammation) confirmed their potential clinical use as diagnostic biomarkers. This research reinforces the growing role of miR-137/hsa-miR-106b in the early diagnosis of myocardial ischemia in unstable angina patients.

LncRNA KCNQ1OT1 knockdown inhibits ox-LDL-induced inflammatory response and oxidative stress in THP-1 macrophages through the miR-137/TNFAIP1 axis.

Both inflammatory response and oxidative stress are regarded as two critical contributors to atherosclerosis. Kcnq1 overlapping transcript 1 (KCNQ1OT1) is an imprinted antisense long non-coding RNA in the kcnq1 locus. Our previous study has demonstrated that KCNQ1OT1 aggravates atherosclerosis by promoting macrophage lipid accumulation. However, its role in atherogenesis remains to be elucidated. This study aimed to observe the impact of KCNQ1OT1 on oxidized low-density lipoprotein (ox-LDL)-induced inflammatory response and oxidative stress and to explore the underlying mechanism. We found that ox-LDL up-regulated KCNQ1OT1 expression in THP-1 macrophages. Knockdown of KCNQ1OT1 increased miR-137 levels, decreased tumor necrosis factor-α-induced protein 1 (TNFAIP1) expression, and inhibited inflammatory response and alleviated oxidative stress in ox-LDL-treated THP-1 macrophages. A ceRNA regulatory network was identified among KCNQ1OT1, miR-137 and TNFAIP1. The inhibitory effect of KCNQ1OT1 knockdown on inflammatory response and oxidative stress was significantly reversed by miR-137 prevention or TNFAIP1 overexpression. In summary, these findings suggest that silencing of KCNQ1OT1 suppresses inflammatory response and oxidative stress induced by ox-LDL through the miR-137/TNFAIP1 pathway in THP-1 macrophages, thereby providing novel mechanistical insights into its pro-atherosclerotic action.

Integrative analysis of cell adhesion molecules in glioblastoma identified prostaglandin F2 receptor inhibitor (PTGFRN) as an essential gene.

BACKGROUND: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults exhibiting infiltration into surrounding tissues, recurrence, and resistance to therapy. GBM infiltration is accomplished by many deregulated factors such as cell adhesion molecules (CAMs), which are membrane proteins that participate in cell-cell and cell-ECM interactions to regulate survival, proliferation, migration, and stemness. METHODS: A comprehensive bioinformatics analysis of CAMs (n = 518) in multiple available datasets revealed genetic and epigenetic alterations among CAMs in GBM. Univariate Cox regression analysis using TCGA dataset identified 127 CAMs to be significantly correlated with survival. The poor prognostic indicator PTGFRN was chosen to study its role in glioma. Silencing of PTGFRN in glioma cell lines was achieved by the stable expression of short hairpin RNA (shRNA) against the PTGFRN gene. PTGFRN was silenced and performed cell growth, migration, invasion, cell cycle, and apoptosis assays. Neurosphere and limiting dilution assays were also performed after silencing of PTGFRN in GSCs. RESULTS: Among the differentially regulated CAMs (n = 181, 34.9%), major proportion of them were found to be regulated by miRNAs (n = 95, 49.7%) followed by DNA methylation (n = 32, 16.7%), and gene copy number variation (n = 12, 6.2%). We found that PTGFRN to be upregulated in GBM tumor samples and cell lines with a significant poor prognostic correlation with patient survival. Silencing PTGFRN diminished cell growth, colony formation, anchorage-independent growth, migration, and invasion and led to cell cycle arrest and induction of apoptosis. At the mechanistic level, silencing of PTGFRN reduced pro-proliferative and promigratory signaling pathways such as ERK, AKT, and mTOR. PTGFRN upregulation was found to be due to the loss of its promoter methylation and downregulation of miR-137 in GBM. PTGFRN was also found to be higher in glioma stem-like cells (GSCs) than the matched differentiated glioma cells (DGCs) and is required for GSC growth and survival. Silencing of PTGFRN in GSCs reduced transcript levels of reprogramming factors (Olig2, Pou3f2, Sall2, and Sox2). CONCLUSION: In this study, we provide a comprehensive overview of the differential regulation of CAMs and the probable causes for their deregulation in GBM. We also establish an oncogenic role of PTGFRN and its regulation by miR-137 in GBM, thus signifying it as a potential therapeutic target.

miR-2682-3p antagonizes its host lncRNA-MIR137HG by interacting with the same target FUS to regulate the progression of gastric cancer.

BACKGROUND: The mechanism of long non-coding RNA MIR137HG in human gastric cancer (GC) is currently unknown. In the present study, we aimed to explore the function and mechanism of MIR137HG in gastric cancer. METHODS: The expression of lncRNA-MIR137HG in 69 gastric cancer samples and their paired surgical margin (SM) tissue samples were tested by QRT-PCR. UCSC was used to find the gene location relationship among MIR137HG and its embedded miRNAs. TargetScan was used to predict the targets of miR-2682-3p. Starbase was used to predict the candidate proteins that interacted with MIR137HG. Western blot, co-focus, and RIP assay were used to verify the direct interaction between MIR137HG and FUS (fused in sarcoma/translocated in liposarcoma, FUS/TLS), while dual-luciferase reporter assay was used to confirm the interaction between miR-2682-3p and FUS. Cell migration assays, colony formation, and xenografts assay were used to investigate the function of MIR137HG and miR-2682-3p to tumor growth and metastasis. Western blot assay was used to explore the downstream candidate protein of FUS. RESULTS: Data showed that MIR137HG expressed significantly higher in GC than in SM. MIR137HG promoted colony formation and migration in vitro and promoted tumor formation and metastasis in vivo. MIR137HG is distributed in both the nucleus and cytoplasm. It was co-located with FUS and could directly interact with FUS, which might interact with other proteins, such as MET(MET-proto-oncogene, receptor tyrosine kinase), RHOC(ras homolog family member), and CTNNB1(catenin beta1). These proteins may involve different signaling pathways to regulate gastric cancer progression. By contrast, the embedded miR-2682-3p could antagonize the series functions of its host lncRNA-MIR137HG by targeting FUS. CONCLUSIONS: lncRNA-MIR137HG promoted growth and metastasis in gastric cancer by interacting with FUS, while miR-2682-3p could inhibit the function of MIR137HG via the same target FUS.

LncRNA-TUG1 promotes the progression of infantile hemangioma by regulating miR-137/IGFBP5 axis.

BACKGROUND: Previous studies indicated that lncRNA taurine upregulated gene 1 (TUG1) played essential roles in human cancers. This study aimed to investigate its function in infantile hemangioma (IH). METHODS: A total of 30 pairs of clinical infantile specimens were used in this study. The expression of TUG1 in IH tissues was assessed by quantitative reverse transcriptase PCR (qRT-PCR). Two short hairpin RNA targeting TUG1 (sh-TUG1-1 and sh-TUG1-2) were transfected into hemangioma-derived endothelial cells, HemECs, to block its expression. The effects of TUG1 on HemECs were evaluated by Cell Counting Kit-8 (CCK-8), colony formation assay, wound healing assay, and Transwell assay. The underlying molecular mechanism of TUG1 was investigated by Starbase prediction and luciferase reporter assay and further determined by loss- and gain-of-function approaches. In addition, the role of TUG1 on tumorigenesis of HemECs was confirmed in an in vivo mouse model. RESULTS: TUG1 was significantly upregulated in infant hemangioma tissues compared with normal adjacent subcutaneous tissues. The loss- and gain-of-function approaches indicated that TUG1 overexpression promoted proliferation, migration, and invasion of HemECs in vitro, and TUG1 knockdown inhibited the tumorigenesis of HemECs in vivo. Specifically, TUG1 could compete with IGFBP5 for miR137 binding. Rescue experiments further confirmed the role of the TUG1/miR137/IGFBP5 axis in HemECs. CONCLUSION: TUG1 was closely associated with the progression of IH by regulating the miR-137/IGFBP5 axis, which might be a potential target for IH treatment.

CircHOMER1 aggravates oxidative stress, inflammation and extracellular matrix deposition in high glucose-induced human mesangial cells.

BACKGROUND: Circular RNAs (circRNAs) play an important regulatory role in human diseases, including diabetic nephropathy (DN). The purpose of this study was to investigate the role and mechanism of circHOMER1 action in DN. METHODS: Human mesangial cells (HMCs) were tested with high glucose (HG) to mimic DN cell models. Quantitative real-time PCR was performed to determine circHOMER1, microRNA (miR)-137 and SRY-box transcription factor 6 (SOX6) expression. SOD activity and MDA level were detected to evaluate cell oxidative stress. ELISA assay was used to analyse the levels of inflammation factors. The protein levels of extracellular matrix (ECM) deposition-related markers and SOX6 were assessed by western blot analysis. The interaction between miR-137 and circHOMER1 or SOX6 was analysed by dual-luciferase reporter assay and RNA pull-down assay. RESULTS: CircHOMER1 was highly expressed in HG-induced HMCs and DN patients. Downregulation of circHOMER1 suppressed oxidative stress, inflammation and ECM deposition in HMCs induced by HG. In terms of mechanism, circHOMER1 could sponge miR-137 to regulate SOX6. Function assays showed that miR-137 inhibitor or SOX6 overexpression revoked the negative regulation of circHOMER1 knockdown on HG-induced HMCs injury. In addition, miR-137 expression was negatively correlated with circHOMER1 and SOX6 expression in DN patients. CONCLUSION: CircHOMER1 promoted HG-induced HMCs oxidative stress, inflammation and ECM accumulation via the miR-137/SOX6 axis, suggesting that circHOMER1 might be a target for DN treatment.

Expression of BDNF-Associated lncRNAs in Parkinson's disease.

Decreased level of neurotrophic factor brain-derived neurotrophic factor (BDNF) has been supposed to participate in the pathoetiology of Parkinson's disease (PD). However, the underlying mechanisms of its dysregulation and the functional network between this factor and other transcripts have not been elucidated. In the current study, we measured expressions of BDNF, and four related long non-coding RNAs, namely BDNF-AS, MIR137HG, MIAT and PNKY in blood of PD patients and normal controls to find their expression levels in these patients and propose a possible mechanism for dysregulation of BDNF in PD patients. Notably, we detected down-regulation of all transcripts in the circulation of PD patients compared with controls. There was no significant difference in expression of either gene between male and female PD patients or patients receiving L-Dopa versus those receiving other drugs. Expression of none of genes was correlated with age, disease duration, disease stage, MMSE or UPDRS. Dynamic principal component analysis showed that expression levels of these genes almost clearly separated samples collected from healthy controls and PD patients into their respective groups. This suggests that the observed lncRNAs differences are associated with the pathophysiology of PD, and these lncRNAs might constitute an important biomarker signature for PD.

Di-n-butyl phthalate promotes monocyte recruitment via miR-137-3p-SP1-MCP-1 pathway.

Since non-covalent bound character and widespread application in numerous products, people are exposed to di-n-butyl phthalate (DBP) at low levels through various ways. Epidemiological studies suggested an association between DBP exposure and atherosclerosis (AS). Still, molecular mechanisms remain unclear. This study aimed to explore the effects of DBP on monocyte recruitment, a key and initial step of AS. EA.hy926 cells were treated with DBP (10-9-10-5 M) or DMSO as control. Chemotaxis assay was applied to investigate THP-1 recruitment. Expression of mRNA /miRNAs and proteins were measured by qRT-PCR and Western blotting, respectively. Levels of monocyte chemotactic protein 1 (MCP-1) in supernatant were detected by ELISA assay. Receptor internalization assay was performed to confirm C-C chemokine receptor type 2 (CCR2) subcellular localization in THP-1 cells and the binding between CCR2 and MCP-1. Dual-luciferase reporter assay was used to analyze the combination between miR-137-3p and specificity protein 1 (SP1), as well as SP1 and MCP-1. Results showed that number of recruited THP-1 cells after EA.hy926 cells treated by DBP was significantly higher than that in the control group due to promoted MCP-1 expression. In addition, expression of MCP-1 was regulated through miR-137-3p-SP1 cascade. Besides, overexpression of miR-137-3p reversed the increased number of recruited THP-1 cells. Our results implied that DBP might promote THP-1 recruitment by targeting miR-137-3p-SP1-MCP-1 in EA.hy926 cells.

High-Throughput Sequencing Reveals Novel microRNAs Involved in the Continuous Flowering Trait of Longan (Dimocarpus longan Lour.).

A major determinant of fruit production in longan (Dimocarpus longan Lour.) is the difficulty of blossoming. In this study, high-throughput microRNA sequencing (miRNA-Seq) was carried out to compare differentially expressed miRNAs (DEmiRNAs) and their target genes between a continuous flowering cultivar 'Sijimi' (SJ), and a unique cultivar 'Lidongben' (LD), which blossoms only once in the season. Over the course of our study, 1662 known miRNAs and 235 novel miRNAs were identified and 13,334 genes were predicted to be the target of 1868 miRNAs. One conserved miRNA and 29 new novel miRNAs were identified as differently expressed; among them, 16 were upregulated and 14 were downregulated. Through the KEGG pathway and cluster analysis of DEmiRNA target genes, three critical regulatory pathways, plant-pathogen interaction, plant hormone signal transduction, and photosynthesis-antenna protein, were discovered to be strongly associated with the continuous flowering trait of the SJ. The integrated correlation analysis of DEmiRNAs and their target mRNAs revealed fourteen important flowering-related genes, including COP1-like, Casein kinase II, and TCP20. These fourteen flowering-related genes were targeted by five miRNAs, which were novel-miR137, novel-miR76, novel-miR101, novel-miR37, and csi-miR3954, suggesting these miRNAs might play vital regulatory roles in flower regulation in longan. Furthermore, novel-miR137 was cloned based on small RNA sequencing data analysis. The pSAK277-miR137 transgenic Arabidopsis plants showed delayed flowering phenotypes. This study provides new insight into molecular regulation mechanisms of longan flowering.

Antagonism between the RNA-binding protein Musashi1 and miR-137 and its potential impact on neurogenesis and glioblastoma development.

RNA-binding proteins (RBPs) and miRNAs are critical gene expression regulators that interact with one another in cooperative and antagonistic fashions. We identified Musashi1 (Msi1) and miR-137 as regulators of a molecular switch between self-renewal and differentiation. Msi1 and miR-137 have opposite expression patterns and functions, and Msi1 is repressed by miR-137. Msi1 is a stem-cell protein implicated in self-renewal while miR-137 functions as a proneuronal differentiation miRNA. In gliomas, miR-137 functions as a tumor suppressor while Msi1 is a prooncogenic factor. We suggest that the balance between Msi1 and miR-137 is a key determinant in cell fate decisions and disruption of this balance could contribute to neurodegenerative diseases and glioma development. Genomic analyses revealed that Msi1 and miR-137 share 141 target genes associated with differentiation, development, and morphogenesis. Initial results pointed out that these two regulators have an opposite impact on the expression of their target genes. Therefore, we propose an antagonistic model in which this network of shared targets could be either repressed by miR-137 or activated by Msi1, leading to different outcomes (self-renewal, proliferation, tumorigenesis).