The lncRNA genomic landscape of oligodendrocytes reveals myelination control by a lncOL1/Suz12 complex in the CNS
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus Rattus norvegicus
PROVIDER: GSE82211 | GEO | 2016/12/28
SECONDARY ACCESSION(S): PRJNA324365
REPOSITORIES: GEO
Similar Datasets
Project description:Long noncoding RNAs (lncRNAs) are emerging as important regulators of cellular functions, but their roles in myelination in the CNS remain undefined. Through de novo transcriptome reconstruction at multiple stages, we establish dynamic expression profiles of lncRNAs during oligodendrocyte lineage progression and uncover a cohort of oligodendrocyte-enriched lncRNAs. Co-expression network analysis reveals a cohort of lncRNAs is linked to protein-coding genes associated with oligodendrocyte maturation. We identify a conserved chromatin-associated oligodendrocyte-restricted lncRNA, lncOL1. Overexpression of lncOL1 promotes oligodendrocyte differentiation in the developing brain, whereas genetic inactivation of lncOL1 causes defects in myelination and remyelination in the CNS. We further show that lncOL1 interacts with Suz12, a component of polycomb repressive complex 2, to promote oligodendrocyte differentiation in part through Suz12-mediated silencing of a differentiation inhibitory network that antagonizes OL maturation. Together, our findings demonstrate lncRNAs as a key layer of the genetic circuitry that controls CNS myelination and myelin repair.
2016-12-28 | GSE82210 | GEO
Project description:Long noncoding RNAs (lncRNAs) are emerging as important regulators of cellular functions, but their roles in myelination in the CNS remain undefined. Through de novo transcriptome reconstruction at multiple stages, we establish dynamic expression profiles of lncRNAs during oligodendrocyte lineage progression and uncover a cohort of oligodendrocyte-enriched lncRNAs. Co-expression network analysis reveals a cohort of lncRNAs is linked to protein-coding genes associated with oligodendrocyte maturation. We identify a conserved chromatin-associated oligodendrocyte-restricted lncRNA, lncOL1. Overexpression of lncOL1 promotes oligodendrocyte differentiation in the developing brain, whereas genetic inactivation of lncOL1 causes defects in myelination and remyelination in the CNS. We further show that lncOL1 interacts with Suz12, a component of polycomb repressive complex 2, to promote oligodendrocyte differentiation in part through Suz12-mediated silencing of a differentiation inhibitory network that antagonizes OL maturation. Together, our findings demonstrate lncRNAs as a key layer of the genetic circuitry that controls CNS myelination and myelin repair.
2016-12-28 | GSE82209 | GEO
Project description:Long noncoding RNAs (lncRNAs) are emerging as important regulators of cellular functions, but their roles in myelination in the CNS remain undefined. Through de novo transcriptome reconstruction at multiple stages, we establish dynamic expression profiles of lncRNAs during oligodendrocyte lineage progression and uncover a cohort of oligodendrocyte-enriched lncRNAs. Co-expression network analysis reveals a cohort of lncRNAs is linked to protein-coding genes associated with oligodendrocyte maturation. We identify a conserved chromatin-associated oligodendrocyte-restricted lncRNA, lncOL1. Overexpression of lncOL1 promotes oligodendrocyte differentiation in the developing brain, whereas genetic inactivation of lncOL1 causes defects in myelination and remyelination in the CNS. We further show that lncOL1 interacts with Suz12, a component of polycomb repressive complex 2, to promote oligodendrocyte differentiation in part through Suz12-mediated silencing of a differentiation inhibitory network that antagonizes OL maturation. Together, our findings demonstrate lncRNAs as a key layer of the genetic circuitry that controls CNS myelination and myelin repair.
2016-12-28 | GSE82165 | GEO
Project description:Long noncoding RNAs (lncRNAs) are emerging as important regulators of cellular functions, but their roles in oligodendrocyte myelination remain undefined. Through de novo transcriptome reconstruction, we establish dynamic expression profiles of lncRNAs at different stages of oligodendrocyte development and uncover a cohort of stage-specific oligodendrocyte-restricted lncRNAs, including a conserved chromatin-associated lncOL1. Co-expression network analyses further define the association of distinct oligodendrocyte-expressing lncRNA clusters with protein-coding genes and predict lncRNA functions in oligodendrocyte myelination. Overexpression of lncOL1 promotes precocious oligodendrocyte differentiation in the developing brain, whereas genetic inactivation of lncOL1 causes defects in CNS myelination and remyelination following injury. Functional analyses illustrate that lncOL1 interacts with Suz12, a component of polycomb repressive complex 2, to promote oligodendrocyte maturation, in part, through Suz12-mediated repression of a differentiation inhibitory network that maintains the precursor state. Together, our findings reveal a key lncRNA epigenetic circuitry through interaction with chromatin-modifying complexes in control of CNS myelination and myelin repair.
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Project description:The lncRNA genomic landscape of oligodendrocytes reveals myelination control by a lncOL1/Suz12 complex in the CNS
| PRJNA324365 | ENA
Project description:The controlling factors that prompt mature oligodendrocytes to myelinate axons are largely undetermined. In this study, we used a forward genetics approach to identify a mutant mouse strain characterized by the absence of CNS myelin despite the presence of abundant numbers of late-stage, process-extending oligodendrocytes. Through linkage mapping and complementation testing, we identified the mutation as a single nucleotide insertion in the gene encoding zinc finger protein 191 (Zfp191), which is a widely expressed, nuclear-localized protein that belongs to a family whose members contain both DNA-binding zinc finger domains and protein-protein-interacting SCAN domains. Zfp191 mutants express an array of myelin-related genes at significantly reduced levels, and our in vitro and in vivo data indicate that mutant ZFP191 acts in a cell-autonomous fashion to disrupt oligodendrocyte function. Therefore, this study demonstrates that ZFP191 is required for the myelinating function of differentiated oligodendrocytes.
| S-EPMC2811831 | biostudies-other
Project description:Myelin is required for rapid nerve signaling and is emerging as a key driver of CNS plasticity and disease. How myelin is built and remodeled remains a fundamental question of neurobiology. Central to myelination is the ability of oligodendrocytes to add vast amounts of new cell membrane, expanding their surface areas by many thousand-fold. However, how oligodendrocytes add new membrane to build or remodel myelin is not fully understood. Here, we show that CNS myelin membrane addition requires exocytosis mediated by the vesicular SNARE proteins VAMP2/3. Genetic inactivation of VAMP2/3 in myelinating oligodendrocytes caused severe hypomyelination and premature death without overt loss of oligodendrocytes. Through live imaging, we discovered that VAMP2/3-mediated exocytosis drives membrane expansion within myelin sheaths to initiate wrapping and power sheath elongation. In conjunction with membrane expansion, mass spectrometry of oligodendrocyte surface proteins revealed that VAMP2/3 incorporates axon-myelin adhesion proteins that are collectively required to form nodes of Ranvier. Together, our results demonstrate that VAMP2/3-mediated membrane expansion in oligodendrocytes is indispensable for myelin formation, uncovering a cellular pathway that could sculpt myelination patterns in response to activity-dependent signals or be therapeutically targeted to promote regeneration in disease.
| S-EPMC9508103 | biostudies-literature
Project description:Oligodendrocytes (OLs) support neurons and signal transmission in the central nervous system (CNS) by enwrapping axons with myelin, a lipid-rich membrane structure. We addressed the significance of fatty acid (FA) synthesis in OLs by depleting FA synthase (FASN) from OL progenitor cells (OPCs) in transgenic mice. While we detected no effects in proliferation and differentiation along the postnatal OL lineage, we found that FASN is essential for accurate myelination, including myelin growth. Increasing dietary lipid intake could partially compensate for the FASN deficiency. Furthermore, FASN contributes to correct myelin lipid composition and stability of myelinated axons. Moreover, we depleted FASN specifically in adult OPCs to examine its relevance for remyelination. Applying lysolecithin-induced focal demyelinating spinal cord lesions, we found that FA synthesis is essential to sustain adult OPC-derived OLs and efficient remyelination. We conclude that FA synthesis in OLs plays key roles in CNS myelination and remyelination.
| S-EPMC6504237 | biostudies-literature
Project description:Treatment of central nervous system (CNS) demyelination is greatly hindered by lack of the knowledge regarding to underlying molecular mechanisms as well as therapeutic agents. Here, we report a novel small molecule agent, gastrodin (GAS), which can significantly promote CNS myelination in in vivo mice models. By using high-throughput sequencing analysis, we discover a key long non-coding RNA Gm7237 that can enhance CNS myelination and is up-regulated by GAS. Through using bioinformatic analysis and experimental validations, we further unravel that microRNA-142a (miR-142a) and its target myelin gene regulatory factor (MRF) is under the direct regulation by Gm7237. Finally, we demonstrate that Gm7237/miR-142a/MRF axis is the key pathway involved in CNS myelination mediated by GAS. Overall, our results provide not only a novel agent for therapeutic treatment of CNS demyelination but also a molecular basis responsible for GAS-promoted CNS myelination.
| S-EPMC8354603 | biostudies-literature
Project description:Myelin is a unique lipid-rich membrane structure that accelerates neurotransmission and supports neuronal function. Sphingolipids are critical myelin components. Yet sphingolipid content and synthesis have not been well characterized in oligodendrocytes, the myelin-producing cells of the CNS. Here, using quantitative real-time PCR, LC-MS/MS-based lipid analysis, and biochemical assays, we examined sphingolipid synthesis during the peak period of myelination in the postnatal rat brain. Importantly, we characterized sphingolipid production in isolated oligodendrocytes. We analyzed sphingolipid distribution and levels of critical enzymes and regulators in the sphingolipid biosynthetic pathway, with focus on the serine palmitoyltransferase (SPT) complex, the rate-limiting step in this pathway. During myelination, levels of the major SPT subunits increased and oligodendrocyte maturation was accompanied by extensive alterations in the composition of the SPT complex. These included changes in the relative levels of two alternative catalytic subunits, SPTLC2 and -3, in the relative levels of isoforms of the small subunits, ssSPTa and -b, and in the isoform distribution of the SPT regulators, the ORMDLs. Myelination progression was accompanied by distinct changes in both the nature of the sphingoid backbone and the N-acyl chains incorporated into sphingolipids. We conclude that the distribution of these changes among sphingolipid family members is indicative of a selective channeling of the ceramide backbone toward specific downstream metabolic pathways during myelination. Our findings provide insights into myelin production in oligodendrocytes and suggest how dysregulation of the biosynthesis of this highly specialized membrane could contribute to demyelinating diseases.
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