Oligodendrocyte intrinsic miR-27a controls myelination and remyelination
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ABSTRACT:
PROVIDER: PRJNA558362 | ENA |
REPOSITORIES: ENA
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Project description:The goal of this study was to understand miR-27a gene regulation in mouse OPCs
2019-08-03 | GSE135308 | GEO
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| S-EPMC6874400 | biostudies-literature
Project description:The progressive loss of CNS myelin in patients with multiple sclerosis (MS) has been proposed to result from the combined effects of damage to oligodendrocytes and failure of remyelination. A common feature of demyelinated lesions is the presence of oligodendrocyte precursors (OLPs) blocked at a premyelinating stage. However, the mechanistic basis for inhibition of myelin repair is incompletely understood. To identify novel regulators of OLP differentiation, potentially dysregulated during repair, we performed a genome-wide screen of 1040 transcription factor-encoding genes expressed in remyelinating rodent lesions. We report that M-bM-^HM-<50 transcription factor-encoding genes show dynamic expression during repair and that expression of the Wnt pathway mediator Tcf4 (aka Tcf7l2) within OLPs is specific to lesionedM-bM-^@M-^Tbut not normalM-bM-^@M-^Tadult white matter. We report that M-NM-2-catenin signaling is active during oligodendrocyte development and remyelination in vivo. Moreover, we observed similar regulation of Tcf4 in the developing human CNS and lesions of MS. Data mining revealed elevated levels of Wnt pathway mRNA transcripts and proteins within MS lesions, indicating activation of the pathway in this pathological context. We show that dysregulation of WntM-bM-^@M-^SM-NM-2-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination, based on (1) conditional activation of M-NM-2-catenin in the oligodendrocyte lineage in vivo and (2) findings from APCMin mice, which lack one functional copy of the endogenous Wnt pathway inhibitor APC. Together, our findings indicate that dysregulated WntM-bM-^@M-^SM-NM-2-catenin signaling inhibits myelination/remyelination in the mammalian CNS. Evidence of Wnt pathway activity in human MS lesions suggests that its dysregulation might contribute to inefficient myelin repair in human neurological disorders. 12 samples total. Two variables in the experiment: genotype (wild type or Olig2cre/DA-Cat) and Developmental stage (Day 4 or Day 15). 4 phenotypes in total with 3 biological replicates for each phenotype.
2009-12-10 | E-GEOD-19403 | biostudies-arrayexpress
Project description:Mutations in Brg1 can cause Coffin-Siris syndrome, where a patient had white matter defects and partial agenesis of the corpus callosum; however, Brg1 functions in CNS myelination and remyelination is unsure. We show that PDGFRa expressed prior than NG2, depletion of Brg1 at PDGFRα+ OPC leads to OPC differentiation restriction and myelin defects, also, Brg1 is critical for oligodendrocyte remyelination. Genomic occupancy and transcriptome analyses indicate that Brg1 promotes H3K27me3 and neuronal genes. Thus our findings reveal that Brg1 is a critical epigenetic programmer of CNS myelination and repair through recruiting H3K27me3 and neuronal genes, suggesting potential strategies of therapeutic intervention for Brg1-associated white matter defects.
2024-03-25 | GSE205236 | GEO
Project description:The function of poly(ADP-ribosyl) polymerase 1 (PARP1) in myelination and remyelination of the central nervous system (CNS) remains enigmatic. Here we report that PARP1 is an intrinsic driver for oligodendroglial development and myelination. Genetic PARP1 depletion impairs the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes and impedes CNS myelination. Mechanistically, PARP1-mediated PARylation activity is not only necessary but also sufficient for OPC differentiation. At the molecular level, we identify the RNA-binding protein Myef2 as a PARylated target which controls OPC differentiation through PARylation-modulated de-repression of myelin protein expression. Furthermore, PARP1’s enzymatic activity is necessary for oligodendrocyte and myelin regeneration after demyelination. Together, our findings suggest that PARP1-mediated PARylation activity may be a potential therapeutic target for promoting OPC differentiation and remyelination in neurological disorders characterized by arrested OPC differentiation and remyelination failure such as multiple sclerosis.
2021-08-16 | GSE181933 | GEO
Project description:The progressive loss of CNS myelin in patients with multiple sclerosis (MS) has been proposed to result from the combined effects of damage to oligodendrocytes and failure of remyelination. A common feature of demyelinated lesions is the presence of oligodendrocyte precursors (OLPs) blocked at a premyelinating stage. However, the mechanistic basis for inhibition of myelin repair is incompletely understood. To identify novel regulators of OLP differentiation, potentially dysregulated during repair, we performed a genome-wide screen of 1040 transcription factor-encoding genes expressed in remyelinating rodent lesions. We report that ∼50 transcription factor-encoding genes show dynamic expression during repair and that expression of the Wnt pathway mediator Tcf4 (aka Tcf7l2) within OLPs is specific to lesioned—but not normal—adult white matter. We report that β-catenin signaling is active during oligodendrocyte development and remyelination in vivo. Moreover, we observed similar regulation of Tcf4 in the developing human CNS and lesions of MS. Data mining revealed elevated levels of Wnt pathway mRNA transcripts and proteins within MS lesions, indicating activation of the pathway in this pathological context. We show that dysregulation of Wnt–β-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination, based on (1) conditional activation of β-catenin in the oligodendrocyte lineage in vivo and (2) findings from APCMin mice, which lack one functional copy of the endogenous Wnt pathway inhibitor APC. Together, our findings indicate that dysregulated Wnt–β-catenin signaling inhibits myelination/remyelination in the mammalian CNS. Evidence of Wnt pathway activity in human MS lesions suggests that its dysregulation might contribute to inefficient myelin repair in human neurological disorders.
2009-12-10 | GSE19403 | GEO
Project description:Citrullination, the deimination of arginine residues into citrulline, has been implicated in the aetiology of several diseases. In multiple sclerosis (MS), citrullination is thought to be a major driver of pathology, through hypercitrullination and destabilization of myelin. As such, inhibition of citrullination has been suggested as a therapeutical strategy for MS. Here we show that citrullination by peptidylarginine deiminase 2 (PADI2) is in contrast required for normal oligodendrocyte differentiation, myelination and motor function. We identify several targets for PADI2, including not only myelin-related proteins, but also several chromatin-associated proteins, implicating PADI2 in epigenetic regulation. Accordingly, we observe that PADI2 inhibition and its knockdown affect chromatin accessibility and prevent the upregulation of genes involved in oligodendrocyte differentiation. Moreover, mice lacking PADI2, display motoric dysfunction and a decreased number of myelinated axons in the corpus callosum. Our study demonstrates that citrullination is required for oligodendrocyte lineage progression and myelination and thus its targeted activation in the oligodendrocyte lineage might be beneficial in the context of remyelination in diseases as MS.
2019-04-23 | GSE115929 | GEO
Project description:Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes. These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention. To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells. Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients. RNA sequencing of oligodendrocyte progenitor cells treated with vehicle, miconazole or clobetasol for 0, 2, 6, or 12 hours. Cells were plated 1.5 hours prior to addition of drug.
2015-04-13 | E-GEOD-63804 | biostudies-arrayexpress
Project description:PRC2 catalyzes tri-methylation of histone H3 lysine residue K27 (H3K27me3), and then H3K27me3 recruits downstream regulatory factors to create a transcriptionally repressive chromatin environment. PRC2 is involved in diverse biological processes, including cell growth, cell differentiation and the maintenance of cell identity. Here, to study the role of PRC2 on oligodendrocyte myelination and remyelination, we performed RNA-seq and ATAC-seq analysis of isolated control and Eed cKO mouse OPCs.
2020-08-17 | GSE135880 | GEO
Project description:In Multiple Sclerosis (MS), inflammatory demyelinated lesions in the brain and spinal cord lead to neurodegeneration and progressive disability. Remyelination can restore fast saltatory conduction and neuroprotection but is inefficient in MS especially with increasing age, and is not yet improvable with therapies. Intrinsic and extrinsic inhibition of oligodendrocyte progenitor cell (OPC) function contributes to remyelination failure, and we hypothesised that the transplantation of ‘improved’ OPCs, genetically edited to overcome these obstacles, could improve remyelination. Here, we edited human(h) embryonic stem cell-derived OPCs to be unresponsive to a chemorepellent released from chronic MS lesions, and transplanted them into rodent models of chronic lesions. Edited hOPCs displayed enhanced migration and remyelination compared to controls, regardless of the host age and length of time post-transplant. This study demonstrates that genetic manipulation and transplantation of hOPCs overcomes the negative environment inhibiting remyelination, with translational implications for therapeutic strategies for people with progressive MS.
2023-08-23 | GSE241451 | GEO