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Aim Gestational diabetes mellitus (GDM) affects a significant number of women worldwide and has been associated with lifelong health consequences for their offspring, including increased susceptibility to obesity, insulin resistance, and type II diabetes. Recent studies have suggested that aberrant expression of the long non-coding RNA Meg3 in the liver may contribute to impaired glucose metabolism in individuals. In this study, we aimed to investigate whether intrauterine exposure to hyperglycemia affects glucose intolerance in puberty by mediating the overexpression of LncMeg3 in the liver. Methods To test our hypothesis, we established an animal model of intrauterine hyperglycemia to mimic GDM. The progeny was observed for phenotypic changes, and intraperitoneal glucose tolerance tests, insulin tolerance tests, and pyruvate tolerance tests were conducted to assess glucose and insulin tolerance. We also measured LncMeg3 expression in the liver using real-time quantitative PCR and examined differential methylation areas (DMRs) in the Meg3 gene using pyrophosphoric sequencing. To investigate the role of LncMeg3 in glucose tolerance, we conducted Meg3 intervention by vein tail and analyzed the changes in the phenotype and transcriptome of the progeny using bioinformatics analysis. Results We found that intrauterine exposure to hyperglycemia led to impaired glucose and insulin tolerance in the progeny, with a tendency toward increased fasting blood glucose in fat offspring at 16 weeks ( P  = 0.0004). LncMeg3 expression was significantly upregulated ( P  = 0.0061), DNMT3B expression downregulated ( P  = 0.0226), and DNMT3A ( P  = 0.0026), TET2 ( P  = 0.0180) expression upregulated in the liver. Pyrophosphoric sequencing showed hypomethylation in Meg3-DMRs ( P  = 0.0005). Meg3 intervention by vein tail led to a decrease in the percentage of obese and emaciated offspring (emaciation: 44% vs. 23%; obesity: 25% vs. 15%) and attenuated glucose intolerance. Bioinformatics analysis revealed significant differences in the transcriptome of the progeny, particularly in circadian rhythm and PPAR signaling pathways. Conclusion In conclusion, our study suggests that hypomethylation of Meg3-DMRs increases the expression of the imprinted gene Meg3 in the liver of males, which is associated with impaired glucose tolerance in GDM-F1. MEG3 interference may attenuate glucose intolerance, which may be related to transcriptional changes. Our findings provide new insights into the mechanisms underlying the long-term effects of intrauterine hyperglycemia on progeny health and highlight the potential of Meg3 as an intervention target for glucose intolerance.

Individuals with diabetes are exposed to a higher risk of perioperative stroke than non-diabetics mainly due to persistent hyperglycemia. LncRNA Meg3 has been considered as an important mediator in regulating ischemic stroke. However, the functional and regulatory roles of Meg3 in diabetic brain ischemic injury remain unclear. In this study, rat brain microvascular endothelial cells (RBMVECs) were exposed to 6 h of oxygen and glucose deprivation (OGD), and subsequent reperfusion via incubating cells with glucose of various high concentrations for 24 h to imitate in vitro diabetic brain ischemic injury. It was shown that the marker events of ferroptosis and increased Meg3 expression occurred after the injury induced by OGD combined with hyperglycemia. However, all ferroptotic events were reversed with the treatment of Meg3-siRNA. Moreover, in this in vitro model, p53 was also characterized as a downstream target of Meg3. Furthermore, p53 knockdown protected RBMVECs against OGD + hyperglycemic reperfusion-induced ferroptosis, while the overexpression of p53 exerted opposite effects, implying that p53 served as a positive regulator of ferroptosis. Additionally, the overexpression or knockdown of p53 significantly modulated GPX4 expression in RBMVECs exposed to the injury induced by OGD combined with hyperglycemic treatment. Furthermore, GPX4 expression was suppressed again after the reintroduction of p53 into cells silenced by Meg3. Finally, chromatin immunoprecipitation assay uncovered that p53 was bound to GPX4 promoter. Altogether, these data revealed that, by modulating GPX4 transcription and expression, the Meg3-p53 signaling pathway mediated the ferroptosis of RBMVECs upon injury induced by OGD combined with hyperglycemic reperfusion.

Cisplatin (DDP) was reported to improve pathological complete response (pCR) rates in triple-negative breast cancer (TNBC) patients, however, the molecular mechanism still remains largely unknown. Emerging evidence suggested that some chemotherapeutic drugs played anti-tumor effects by inducing cell pyroptosis. Nevertheless, whether pyroptosis contributes to the DDP-induced anti-tumor effect in TNBC remains unexploited. In the present study, NLRP3/caspase-1/GSDMD pyroptosis pathway was involved in the DDP-induced anti-tumor effect of TNBC and , providing evidence that DDP might induce pyroptosis in TNBC. Moreover, DDP activated NLRP3/caspase-1/GSDMD pyroptosis pathway by up-regulating the long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3). Furthermore, knockdown of MEG3 not only partly abolished the activation effect of DDP on NLRP3/caspase-1/GSDMD pathway-mediated pyroptosis, but also reversed the suppression of DDP on tumor growth and metastasis ability and further confirming that MEG3 may partially mediate the pyroptotic signaling upon DDP treatment. Thus, our data uncovered a novel mechanism that DDP induced pyroptosis via activation of MEG3/NLRP3/caspase-1/GSDMD pathway in TNBC to exert anti-tumor effects, which may help to develop new strategies for the therapeutic interventions in TNBC.

Long noncoding RNAs (lncRNAs) regulate gene expression by association with chromatin, but how they target chromatin remains poorly understood. We have used chromatin RNA immunoprecipitation-coupled high-throughput sequencing to identify 276 lncRNAs enriched in repressive chromatin from breast cancer cells. Using one of the chromatin-interacting lncRNAs, MEG3 , we explore the mechanisms by which lncRNAs target chromatin. Here we show that MEG3 and EZH2 share common target genes, including the TGF-β pathway genes. Genome-wide mapping of MEG3 binding sites reveals that MEG3 modulates the activity of TGF-β genes by binding to distal regulatory elements. MEG3 binding sites have GA-rich sequences, which guide MEG3 to the chromatin through RNA–DNA triplex formation. We have found that RNA–DNA triplex structures are widespread and are present over the MEG3 binding sites associated with the TGF-β pathway genes. Our findings suggest that RNA–DNA triplex formation could be a general characteristic of target gene recognition by the chromatin-interacting lncRNAs. Long noncoding RNAs (lncRNAs) regulate gene expression by association with chromatin. Here, the authors show that lncRNA MEG3 regulates the TGF-β pathway by bridging the interactions between polycomb repressive complex 2 and the distal regulatory elements of the TGF-β pathway genes via formation of RNA–DNA triplexes.

Aberrant expression of MEG3 has been shown in various cancers. The purpose of this study is to evaluate the effect of MEG3 on glioma cells and the use of potential chemotherapeutics in glioma by modulating MEG3 expression. Cell viability, migration and chemosensitivity were assayed. Cell death was evaluated in MEG3 overexpressing and MEG3 suppressed cells. MEG3 expression was compared in patient‐derived glioma cells concerning IDH1 mutation and WHO grades. Silencing of MEG3 inhibited cell proliferation and reduced cell migration while overexpression of MEG3 promoted proliferation in glioma cells. MEG3 inhibition improved the chemosensitivity of glioma cells to 5‐fluorouracil (5FU) but not to navitoclax. On the other hand, there is no significant effect of MEG3 expression on temozolamide (TMZ) treatment which is a standard chemotherapeutic agent in glioma. Suppression of the MEG3 gene in patient‐derived oligodendroglioma cells also showed the same effect whereas glioblastoma cell proliferation and chemosensitivity were not affected by MEG3 inhibition. Further, as a possible cell death mechanism of action apoptosis was investigated. Although MEG3 is a widely known tumour suppressor gene and its loss is associated with several cancer types, here we reported that MEG3 inhibition can be used for improving the efficiency of known chemotherapeutic drug sensitivity. We propose that the level of MEG3 should be evaluated in the treatment of different glioma subtypes that are resistant to effective drugs to increase the potential effective drug applications.

Long non-coding RNAs (lncRNAs) play important roles in diverse biological processes, such as cell growth, apoptosis and migration. Although downregulation of lncRNA MEG3 has been identified in several cancers, little is known about its role in esophageal squamous cell carcinoma (ESCC). The aim of the present study was to detect MEG3 expression in clinical ESCC tissues, investigate its biological functions and the endoplasmic reticulum (ER) stress-relative mechanism. MEG3 expression levels were detected by qRT-PCR in both tumor tissues and adjacent non-tumor tissues from 28 ESCC patients. pcDNA3.1-MEG3 recombinant plasmids were constructed and transfected to EC109 cells. Cell growth was analyzed by CCK-8 assay. Cell apoptosis was analyzed by fluorescence microscope and Annexin V/PI assay. The protein expression was determined by western blot analysis. The results showed that MEG3 decreased significantly in ESCC tissues relative to adjacent normal tissues. pcDNA3.1-MEG3 plasmids were successfully constructed and the expression level of MEG3 significantly increased after MEG3 transfection to EC109 cells. Ectopic expression of MEG3 inhibited EC109 cell proliferation and induced apoptosis in vitro. MEG3 overexpression increased the expression of ER stress-related proteins (GRP78, IRE1, PERK, ATF6, CHOP and cleaved-caspase-3). Our results first demonstrate that MEG3 is downregulated in ESCC tissues. MEG3 was able to inhibit cell growth and induced apoptosis in EC109 cells, most probably via activation of the ER stress pathway.

This study was designed to detecting the influences of lncRNA MEG3 in prostate cancer. Aberrant lncRNAs expression profiles of prostate cancer were screened by microarray analysis. The qRT‐PCR and Western blot were employed to investigating the expression levels of lncRNA MEG3, miR‐9‐5p and QKI‐5. The luciferase reporter assay was utilized to testifying the interactions relationship among these molecules. Applying CCK‐8 assay, wound healing assay, transwell assay and flow cytometry in turn, the cell proliferation, migration and invasion abilities as well as apoptosis were measured respectively. LncRNA MEG3 was a down‐regulated lncRNA in prostate cancer tissues and cells and could inhibit the expression of miR‐9‐5p, whereas miR‐9‐5p down‐regulated QKI‐5 expression. Overexpressed MEG3 and QKI‐5 could decrease the abilities of proliferation, migration and invasion in prostate cancer cells effectively and increased the apoptosis rate. On the contrary, miR‐9‐5p mimics presented an opposite tendency in prostate cancer cells. Furthermore, MEG3 inhibited tumour growth and up‐regulated expression of QKI‐5 in vivo. LncRNA MEG3 was a down‐regulated lncRNA in prostate cancer and impacted the abilities of cell proliferation, migration and invasion, and cell apoptosis rate, this regulation relied on regulating miR‐9‐5p and its targeting gene QKI‐5.

Within the non-coding genome landscape, long non-coding RNAs (lncRNAs) and their secretion within exosomes are a window that could further explain the regulation, the sustaining, and the spread of lung diseases. We present here a compilation of the current knowledge on lncRNAs commonly found in Chronic Obstructive Pulmonary Disease (COPD), asthma, Idiopathic Pulmonary Fibrosis (IPF), or lung cancers. We built interaction networks describing the mechanisms of action for COPD, asthma, and IPF, as well as private networks for H19, MALAT1, MEG3, FENDRR, CDKN2B-AS1, TUG1, HOTAIR, and GAS5 lncRNAs in lung cancers. We identified five signaling pathways targeted by these eight lncRNAs over the lung diseases mentioned above. These lncRNAs were involved in ten treatment resistances in lung cancers, with HOTAIR being itself described in seven resistances. Besides, five of them were previously described as promising biomarkers for the diagnosis and prognosis of asthma, COPD, and lung cancers. Additionally, we describe the exosomal-based studies on H19, MALAT1, HOTAIR, GAS5, UCA1, lnc-MMP2-2, GAPLINC, TBILA, AGAP2-AS1, and SOX2-OT. This review concludes on the need for additional studies describing the lncRNA mechanisms of action and confirming their potential as biomarkers, as well as their involvement in resistance to treatment, especially in non-cancerous lung diseases.

Skeletal muscle plays a crucial role in maintaining motor function and metabolic homeostasis, with its loss or atrophy leading to significant health consequences. Long non‐coding RNAs (lncRNAs) have emerged as key regulators in muscle biology; however, their precise roles in muscle function and pathology remain to be fully elucidated. This study demonstrates that lncRNA maternally expressed gene 3 (MEG3) is preferentially expressed in slow‐twitch muscle fibers and dynamically regulated during muscle development, aging, and in the context of Duchenne muscular dystrophy (DMD). Using both loss‐ and gain‐of‐function mice models, this study shows that lncRNA‐MEG3 is critical for preserving muscle mass and function. Its depletion leads to muscle atrophy, mitochondrial dysfunction, and impaired regenerative capacity, while overexpression enhances muscle mass, increases oxidative muscle fiber content, and improves endurance. Notably, lncRNA‐MEG3 overexpression in MDX mice significantly alleviates muscle wasting and adipose tissue infiltration. Mechanistically, this study uncovers a novel interaction between lncRNA‐MEG3 and the polycomb repressive complex 2 (PRC2), where lncRNA‐MEG3 binds to SUZ12 polycomb repressive complex 2 subunit (Suz12), stabilizes PRC2, facilitates SUZ12 liquid–liquid phase separation (LLPS), and regulates the epigenetic modulation of four and a half lim domains 3 (Fhl3) and ring finger protein 128 (Rnf128). These findings not only highlight the crucial role of lncRNA‐MEG3 in muscle homeostasis but also provide new insights into lncRNA‐based therapeutic strategies for muscle‐related diseases. This study has identified lncRNA‐MEG3 as a key regulator of muscle mass, promoting slow‐twitch muscle fibers and preventing muscle atrophy. By stabilizing the SUZ12/PRC2 complex through liquid–liquid phase separation (LLPS), lncRNA‐MEG3 influences mitochondrial function and lipid metabolism. These findings highlight its potential as a therapeutic target for muscle‐wasting diseases like Duchenne muscular dystrophy (DMD).