Identification of miRNA, lncRNA and mRNA-associated ceRNA networks and potential biomarker for MELAS with mitochondrial DNA A3243G mutation
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ABSTRACT:
PROVIDER: PRJNA350207 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR4445638.fastq.gz | Fastqsanger.gz | |||
| SRR4445639.fastq.gz | Fastqsanger.gz |
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Project description:To elucidate the regulating networks of dysregulated ncRNAs in Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) with m.A3243G mutation.
2016-10-23 | GSE89065 | GEO
Project description:To elucidate the regulating networks of dysregulated ncRNAs in Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) with m.A3243G mutation.
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Project description:Researchers in the field of mitochondrial biology are increasingly unveiling of the complex mechanisms between mitochondrial dysfunction and noncoding RNAs (ncRNAs). However, roles of ncRNAs underlying mitochondrial myopathy remain unexplored. The aim of this study was to elucidate the regulating networks of dysregulated ncRNAs in Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) with mitochondrial DNA (mtDNA) A3243G mutation, which might make contributions to the unveiling of the complex mechanisms underlying mitochondrial myopathy and, possibly, new tools applicable to clinical practice. Through high-throughput technology followed by quantitative real-time polymerase chain reaction (qRT-PCR) and bioinformatics analyses, for the first time, we found that the dysregulated muscle miRNAs and lncRNAs between 20 MELAS patients with mtDNA A3243G mutation and 20 controls formed complex regulation networks and participated in immune system, signal transduction, translation, muscle contraction and other pathways in discovery and training phase. Then, selected ncRNAs were validated in muscle and serum in independent validation cohorts by qRT-PCR. Finally, ROC curve analysis indicated reduced serum miR-27b-3p had the better diagnosis value than lactate and might serve as a novel, noninvasive biomarker for MELAS. Follow-up investigation is warranted to better understand roles of ncRNAs in mitochondrial myopathy pathogenesis.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2016-10-23 | GSE89066 | GEO
Project description:Background: The heteroplasmic mitochondrial DNA (mtDNA) mutation A3243G causes the MELAS syndrome as one of the most frequent mitochondrial diseases. The process of reconfiguration of nuclear gene expression profile to accommodate cellular processes to the functional status of mitochondria might be a key to MELAS disease manifestation and could contribute to its diverse phenotypic presentation. Objective: To determine master regulatory protein networks and disease-modifying genes in MELAS syndrome. Methods: Analyses of whole blood transcriptomes from 10 MELAS patients using a novel strategy by combining classic Affymetrix oligonucleotide microarray profiling with regulatory and protein interaction network analyses. Results and Interpretation: Hierarchical cluster analysis elucidated that the relative abundance of mutant mtDNA molecules is decisive for the nuclear gene expression response. Further analyses confirmed not only transcription factors already known to be involved in mitochondrial diseases (such as TFAM), but also detected the hypoxia-inducible factor 1α (HIF-1α)/HIF-1β complex, nuclear factor Y (NF-Y) and CREB-related transcription factors as novel master regulators for reconfiguration of nuclear gene expression in response to the MELAS mutation. Correlation analyses of gene alterations and clinico-genetic data detected significant correlations between A3243G-induced nuclear gene expression changes and mutant mtDNA load as well as disease characteristics. These potential disease-modifying genes influencing the expression of the MELAS phenotype are mainly related to clusters primarily unrelated to cellular energy metabolism, but important for nucleic acid and protein metabolism, and signal transduction. Our data thus provide a framework to search for new pathogenetic concepts and potential therapeutic approaches to treat the MELAS syndrome. Peripheral blood samples were collected from ten A3243G MELAS patients and twenty age- and sex-matched healthy controls (2 controls for each patient). The patient cohort consisted of 4 females and 6 males, mean±s.e.m. age was 44.1±11.9 years (range: 22–63 years), mean±s.e.m. age at disease onset was 27.1±4.9 years (range: 13–55 years), mean±s.e.m. disease duration was 19.0±4.7 years (range: 4–43 years), and disease severity measured by the ‘Newcastle Mitochondrial Disease Adult Scale’ (NMDAS) 8 ranging from 0.0 (no symptoms) to 1.0 (maximum score) was 0.26±0.05 (range: 0.02–0.54).
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Project description:The development of mitochondrial medicine is greatly impaired by the lack of knowledge and identification of efficient therapeutic routes targeting mitochondria. To better understand the pathophysiology of MELAS syndrome, neuronal cybrid cells, carrying different mutant loads of the m.3243A>G mutation, were investigated by a metabolomics and transcriptomics combined approach. Specific signatures, identifying MELAS biochemical biomarkers, disclosed the glutamate pathway as a culprit mechanism, establishing a strong correlation between glutamate concentrations and the m.3243A>G heteroplasmy levels. Transcriptomic analyses further revealed peculiar gene clusters, including glutamate, gamma-aminobutyric acid (GABA) and tricarboxylic acid (TCA) cycle pathways. These results were supported by post-mortem brain tissue analysis of a MELAS patient, confirming the dysregulation of the glutamate metabolic pathway. Ketogenic diet known to reduce glutamate toxicity, induced a significant reduction of glutamate level after 48h of ketone body treatment, improved mitochondrial functions alleviating the accumulation of several intermediate metabolites of the TCA cycle in MELAS cells. Thus, the integrated approach using a multi-OMICs strategy on MELAS cybrid cells, disclosed novel insights in the mitochondrial energy failure, identifying glutamate as a potential biomarker of the disease, while highlighting ketogenic diet, a nutrition based strategy, to treat MELAS patients
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Project description:Background: The heteroplasmic mitochondrial DNA (mtDNA) mutation A3243G causes the MELAS syndrome as one of the most frequent mitochondrial diseases. The process of reconfiguration of nuclear gene expression profile to accommodate cellular processes to the functional status of mitochondria might be a key to MELAS disease manifestation and could contribute to its diverse phenotypic presentation. Objective: To determine master regulatory protein networks and disease-modifying genes in MELAS syndrome. Methods: Analyses of whole blood transcriptomes from 10 MELAS patients using a novel strategy by combining classic Affymetrix oligonucleotide microarray profiling with regulatory and protein interaction network analyses. Results and Interpretation: Hierarchical cluster analysis elucidated that the relative abundance of mutant mtDNA molecules is decisive for the nuclear gene expression response. Further analyses confirmed not only transcription factors already known to be involved in mitochondrial diseases (such as TFAM), but also detected the hypoxia-inducible factor 1α (HIF-1α)/HIF-1β complex, nuclear factor Y (NF-Y) and CREB-related transcription factors as novel master regulators for reconfiguration of nuclear gene expression in response to the MELAS mutation. Correlation analyses of gene alterations and clinico-genetic data detected significant correlations between A3243G-induced nuclear gene expression changes and mutant mtDNA load as well as disease characteristics. These potential disease-modifying genes influencing the expression of the MELAS phenotype are mainly related to clusters primarily unrelated to cellular energy metabolism, but important for nucleic acid and protein metabolism, and signal transduction. Our data thus provide a framework to search for new pathogenetic concepts and potential therapeutic approaches to treat the MELAS syndrome.
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Project description:Adiponectin (APN) is an endogenous adipokine secreted from adipocytes that exerts an anti-inflammation property. AdipoAI is an orally active adiponectin receptor agonist identified by our group, which can emulate APN's anti-inflammatory properties through mechanisms not fully understood. To explore AdipoAI function, we used lncRNA microarray and got differential lncRNA/mRNA expression medicated by AdipoAI. Identified as one kind of non-coding RNA with more than 200bp length, lncRNA has been demonstrated to have abundance biological functions, including anti-inflammatory response. In the current study, we performed an lncRNA microarray in LPS-induced Raw264.7 cells which pre-stimulated with AdipoAI, and screened 110 DElncRNAs and 190 DEmRNAs. Enrichment analyses were conducted to total mRNAs and DEmRNAs, including GSVA, ssGSEA, GO/KEGG, GSEA and PPI analysis. Among all these processes, endocytosis was significantly enriched. A co-expression analysis was built based on DElncRNAs and DEmRNAs. Then, using Targetscan and miRwalk to predict related microRNAs of DElncRNAs and DEmRNAs respectively, we established competing endogenous RNA (ceRNA) networks including 54 mRNAs from 8 GO items. Furthermore, 33 m6A methylation related marker genes were obtained from previous study and used for the construction of m6A related-lncRNA network using the co-expression analysis. We identified FTO as the hub gene of the network, and 14 lncRNAs that interacted with it. The expression levels of 10 lncRNAs selected from ceRNA and FTO- related lncRNAs networks were validated with qRT-PCR. Finally, Macrophage phenotype scores showed that AdipoAI could attenuate the M2b and M2c polarization of macrophage and correlate with the above lncRNAs. Our work reveals that lncRNA might involve in the anti-inflammation process of AdipoAI in LPS-induced macrophages through ceRNA network and epigenetic regulation of m6A. Mechanistically, these lncRNAs associated with AdipoAI might be related to endocytosis and polarization in macrophage, and provide new candidates for the anti-inflammatory application of APN and its receptor agonist.
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