MiR-219 Cooperates with miR-338 in Myelination and Promotes Myelin Repair in the CNS
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: GSE80439
PROVIDER: PRJNA318906 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3402470.fastq.gz | Fastqsanger.gz | |||
| SRR3402471.fastq.gz | Fastqsanger.gz | |||
| SRR3402472.fastq.gz | Fastqsanger.gz | |||
| SRR3402473.fastq.gz | Fastqsanger.gz | |||
| SRR3402474.fastq.gz | Fastqsanger.gz |
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Project description:microRNAs (miRNAs) have been implicated in oligodendrogenesis and demyelinating diseases; however, identification of individual miRNAs responsible has remained elusive. Through targeted mutagenesis, we find that miR-219 is required for proper oligodendrocyte differentiation and myelination in vivo. Deletion of miR-338 together with miR-219 further exacerbates hypomyelination phenotypes. Temporally specific ablation reveals a critical role for miR-219 in oligodendrocyte remyelination after demyelination, while overexpression of miR-219 promotes precocious oligodendrocyte maturation and myelin regeneration. Accordingly, administration of miR-219 mimics to lysolecithin-induced demyelinating lesions in the murine spinal cord and brain enhances myelin restoration. Through integrating analyses of transcriptome profiling and biotin-affinity miRNA pull-down, we identify a set of stage-specific targets of miR-219, including Etv5 and Lingo1, as oligodendrocyte differentiation inhibitors. Inhibiting Etv5 and Lingo1 leads to a partial rescue of differentiation defects observed in miR-219-mutant OLs in vitro. Together, our findings identify context-specific miRNA-regulated checkpoints that control CNS myelinogenesis and myelin repair.
2017-04-21 | GSE80439 | GEO
Project description:A lack of sufficient oligodendrocyte myelination contributes to remyelination failure in demyelinating disorders. miRNAs have been implicated in oligodendrogenesis; however, their functions in myelin regeneration remained elusive. Through developmentally regulated targeted mutagenesis, we demonstrate that miR-219 alleles are critical for CNS myelination and remyelination after injury. Further deletion of miR-338 exacerbates the miR-219 mutant hypomyelination phenotype. Conversely, miR-219 overexpression promotes precocious oligodendrocyte maturation and regeneration processes in transgenic mice. Integrated transcriptome profiling and biotin-affinity miRNA pull-down approaches reveal stage-specific miR-219 targets in oligodendrocytes and further uncover a novel network for miR-219 targeting of differentiation inhibitors including Lingo1 and Etv5. Inhibition of Lingo1 and Etv5 partially rescues differentiation defects of miR-219-deficient oligodendrocyte precursors. Furthermore, miR-219 mimics enhance myelin restoration following lysolecithin-induced demyelination as well as experimental autoimmune encephalomyelitis, principal animal models of multiple sclerosis. Together, our findings identify context-specific miRNA-regulated checkpoints that control myelinogenesis and a therapeutic role for miR-219 in CNS myelin repair.
| S-EPMC5569304 | biostudies-literature
Project description:Understanding the regulation of oligodendrocyte development and myelination in the central nervous system (CNS) is essential, not only to facilitate myelin repair but also to define the role of oligodendrocytes in maintaining axonal integrity. In vitro studies have implicated astrocytes in influencing multiple aspects of oligodendrocytes and their precursors, however the in vivo role of astrocytes in myelination and myelin repair remain poorly defined. We show that astrocyte ablation during postnatal spinal cord development resulted in a concomitant delay in myelination, demonstrating a critical role for astrocytes in promoting developmental myelination. By contrast, in the adult CNS, localized ablation of astrocytes 2 days after a demyelinating insult resulted in increased numbers of oligodendrocytes and accelerated remyelination in both the spinal cord and the corpus callosum. Microarray analysis reveals astrocytic NF-kB signaling pathway as a major contributor to pathological events occurring after demyelination. We suggest that the localized functions of astrocytes are fundamentally different during developmental myelination and myelin repair. Astrocytes are critical for developmental myelination, however in a demyelinating environment they are detrimental to myelin repair.
2017-08-01 | GSE60276 | GEO
Project description:Purpose: RNA sequencing of spinal cord following intranasal administration of miRNA-219 in Theiler’s murine encephalomyelitis virus (TMEV) model of multiple sclerosis Methods: RNA isolated from spinal cords was analyzed by Next-Generation RNA Sequencing (Illumina) Results: Here, we analyzed the therapeutic effects of miR-219 in a virus-induced demyelinating model. Following intranasal administration of miR-219 in TMEV-infected mice, we found significant reduction of clinical signs, virus persistence (virus genome copy numbers), neuroglia activation, proinflammatory cytokine levels, and demyelination. RNA sequencing of expressed host genes demonstrated that miR-219 potentiates transcriptional changes in cholesterol-related genes, leading to reduced levels of this lipid. Conclusions: Since virus replication relies on hijacking cholesterol biosynthesis and trafficking of host cell endogenous pools as well as remodeling intracellular membranes, i.e., the virus replication organelles or viroplasm, treatment with miR-219 may interfere with virus RNA replication through downregulation of cholesterol synthesis. Our findings show that miR-219 administration lessens pathological changes by reducing the CNS virus loads and favoring myelin repair.
2020-11-16 | GSE107091 | GEO
Project description:The transcriptional control of CNS myelin gene expression is poorly understood. Here we identify gene model 98, which we have named Myelin-gene Regulatory Factor (MRF), as a transcriptional regulator required for CNS myelination. Within the CNS, MRF is specifically expressed by postmitotic oligodendrocytes. MRF is a nuclear protein containing an evolutionarily conserved DNA binding domain homologous to a yeast transcription factor. Knockdown of MRF in oligodendrocytes by RNA interference prevents expression of most CNS myelin genes; conversely, overexpression of MRF within cultured oligodendrocyte progenitors or the chick spinal cord promotes expression of myelin genes. In mice lacking MRF within the oligodendrocyte lineage, pre-myelinating oligodendrocytes are generated but display severe deficits in myelin gene expression and fail to myelinate. These mice display severe neurological abnormalities, and die due to seizures during the third postnatal week. These findings establish MRF as a critical transcriptional regulator essential for oligodendrocyte maturation and CNS myelination. We used microarrays to compare cultured oligodendrocytes (differentiated in vitro for 4 days) from MRF conditional knockouts and control litteramates to look at the effects of MRF deficiency on myelin gene expression. Mouse OPCs grown in vitro in the presence of PDGF serve as a baseline for gene expression prior to differentiation.
2009-05-31 | GSE15303 | GEO
Project description:Among the fundamental unresolved questions in psychiatry is why symptoms of psychosis, such as auditory hallucinations in schizophrenia, fail to appear until early adulthood. Here we report that in mouse models of 22q11.2 deletion syndrome (22q11DS), a leading genetic cause of schizophrenia, synaptic transmission at thalamocortical inputs to the auditory cortex becomes disrupted later in life, thereby recapitulating the adult onset of psychosis. Age-dependent disruption of thalamocortical synaptic transmission in 22q11DS is mediated by dopamine receptor Drd2-targeting microRNA miR-338-3p, which is enriched in the thalamus but becomes depleted due to haploinsufficiency of the microRNA-processing 22q11DS gene Dgcr8. Deletion/knockdown of miR-338-3p causes the Drd2 increase in the auditory thalamus and abnormal sensitivity of 22q11DS thalamocortical inputs to antipsychotics, replicates auditory synaptic and behavioral abnormalities in 22q11DS, and eliminates age dependence of these auditory deficits. These results suggest that miR-338-3p mediates the pathogenic mechanism of 22q11DS-related psychosis and controls its late onset.
2016-10-10 | GSE73981 | GEO
Project description:SPINK1 overexpression defines the second largest subtype of prostate cancer (PCa), however molecular mechanisms underlying its upregulation remains poorly understood. Here, we identified the role of miR-338-5p and miR-421 in post-transcriptional regulation of SPINK1. We established that miR-338-5p/miR-421 mediates several cellular responses against SPINK1-positive cancer by targeting oncogenic long non-coding RNA (lncRNA) MALAT1, inducing cell-cycle arrest, inhibiting epithelial-to-mesenchymal transition (EMT), cancer-stemness and drug resistance. Moreover, ectopic expression of miR-338-5p/miR-421 abrogates SPINK1-mediated oncogenesis, tumor growth and distant metastases in murine model. Importantly, RNA-sequencing expression analysis revealed an inverse correlation between miRNAs and SPINK1 or MALAT1 in PCa patients’ specimens. Further, we demonstrate Polycomb group protein EZH2-mediated epigenetic silencing of miR-338-5p/miR-421 in SPINK1-positive subtype. Thus, restoring miR-338-5p/miR-421 expression using epigenetic drugs or synthetic mimics could abrogate SPINK1-mediated oncogenesis by targeting multiple oncogenic pathways and eliciting anti-cancer pleiotropic effects. Taken together, the present study unravels the molecular mechanism underlying SPINK1 overexpression and suggests miR-338-5p and miR-421 replacement therapy for the treatment of SPINK1-positive malignancies.
2018-12-30 | GSE108558 | GEO
Project description:The transcriptional control of CNS myelin gene expression is poorly understood. Here we identify gene model 98, which we have named Myelin-gene Regulatory Factor (MRF), as a transcriptional regulator required for CNS myelination. Within the CNS, MRF is specifically expressed by postmitotic oligodendrocytes. MRF is a nuclear protein containing an evolutionarily conserved DNA binding domain homologous to a yeast transcription factor. Knockdown of MRF in oligodendrocytes by RNA interference prevents expression of most CNS myelin genes; conversely, overexpression of MRF within cultured oligodendrocyte progenitors or the chick spinal cord promotes expression of myelin genes. In mice lacking MRF within the oligodendrocyte lineage, pre-myelinating oligodendrocytes are generated but display severe deficits in myelin gene expression and fail to myelinate. These mice display severe neurological abnormalities, and die due to seizures during the third postnatal week. These findings establish MRF as a critical transcriptional regulator essential for oligodendrocyte maturation and CNS myelination. We used microarrays to compare cultured oligodendrocytes (differentiated in vitro for 4 days) from MRF conditional knockouts and control litteramates to look at the effects of MRF deficiency on myelin gene expression. Mouse OPCs grown in vitro in the presence of PDGF serve as a baseline for gene expression prior to differentiation. Mouse OPCs from MRF conditional knockout (MRF fl/fl, Olig2 wt/cre) mice and control littermates (MRF wt/fl; Olig2 wt/cre) were isolated from enzymatically dissociated P7 mouse brains as previously described (Cahoy et al., 2008), positively immunopanning for PDGFR-alpha following a depletion of microglia with BSL1. Cells were grown in defined serum-free media as previously described (Dugas et al., 2006), but with the addition of 2% B-27 (Invitrogen). Cells were proliferated for several days in the presence of PDGF-AA (10 ng/ml, PeproTech) and then differentiation induced by withdrawal of PDGF-AA and addition of triiodothyronine (T3) (40 ng/ml; Sigma). RNA was isolated from cells 4 days after induction of differentiation; OPCs maintained in PDGF-AA serve as a baseline of OPC gene expression. Total RNA was isolated from cells with the RNeasy micro kit (Qiagen, Valencia, CA) using Qiagen on-column DNase treatment to remove any contaminating genomic DNA. The integrity of RNA was assessed using an Agilent 2100 Bioanalyzer (Agilent Technologies) and RNA concentration was determined using a NanoDrop ND-1000 spectrophotometer (NanoDrop, Rockland, DE). Biotinylated cRNAs for hybridization to Affymetrix 3'-arrays were prepared from 1ug total RNA using the Affymetrix two-cycle target labeling assay with spike in controls (Affymetrix Inc., Santa Clara, CA, 900494). Labeled-cRNA was fragmented and hybridized to Mouse Genome 430 2.0 Arrays (3'-arrays, Affymetrix, 900495) following the manufacturer's protocols. Raw image files were processed using Affymetrix GCOS 1.3 software to calculate individual probe cell intensity data and generate CEL data files. Using GCOS and the MAS 5.0 algorithm, intensity data was normalized per chip to a target intensity TGT value of 500 and expression data and present/absent calls for individual probe sets calculated. Gene symbols and names for data analyzed with the MAS 5.0 algorithm were from the Affymetrix Netaffx Mouse430_2 annotations file (http://www.affymetrix.com/support/technical/byproduct.affx?product=moe430-20). Quality control was performed by examining raw DAT image files for anomalies, confirming each GeneChip array had a background value less than 100, monitoring that the percencelle present calls was appropriate for the cell type, and inspecting the poly(A) spike in controls, housekeeping genes, and hybridization controls to confirm labeling and hybridization consistency.
2009-05-31 | E-GEOD-15303 | biostudies-arrayexpress
Project description:Myelin, the insulating sheath that surrounds neuronal axons, is produced by oligodendrocytes in the central nervous system (CNS). This evolutionary innovation, which first appears in jawed vertebrates, enabled rapid transmission of nerve impulses, more complex brains and greater morphological diversity. Here we report that RNA level expression of RNLTR12-int, a retrotransposon of retroviral origin, is essential for myelination. We show RNLTR12-int-encoded non-coding RNA binds to the transcription factor SOX10 to regulate transcription of myelin basic protein (Mbp, the major constituent of myelin) in rodents. RNLTR12-int like sequences (which we nameRetroMyelin) are found in all jawed-vertebrates and we further demonstrate their function in regulating myelination in two different vertebrate phyla (zebrafish and frogs). Our study therefore suggests that retroviral endogenization was a key step in the emergence of vertebrate myelin.
2024-02-14 | GSE237744 | GEO
Project description:To investigate the miR-219-5p decreases the resistance of OC cells to cisplatin via Wnt/β-catenin signaling and autophagy by regulating HMGA2, we tested the A2780 and A2780-DDP cell lines with miRNA-Seq.
2022-07-30 | GSE209922 | GEO