From OPC to Oligodendrocyte: An Epigenetic Journey

Tiane, Assia; Schepers, Melissa; Rombaut, Ben; Hupperts, Raymond; Prickaerts, Jos; Hellings, Niels; Hove, Daniël L.A. van den; Vanmierlo, Tim

doi:10.3390/cells8101236

Cited by 87 publications

(95 citation statements)

References 172 publications

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“…Oligodendrocytes are the myelin-producing cells of the CNS, and repairing demyelinated lesions in MS critically rests on the recruitment of fresh OPCs into the damaged region and their successful differentiation into mature, myelinating oligodendrocytes. This process of differentiation is tightly regulated by several factors, including transcriptional control, exogenous signalling from molecules like cytokines, chemokines and neurotransmitters [ 82 , 90 ], as well as epigenetic mechanisms that have been reviewed recently [ 91 ]. Here, we specifically focus on the contribution of microRNAs in this process.…”

Section: Contribution Of Mirnas To Remyelination In Cns Cellsmentioning

confidence: 99%

The Role of MicroRNAs in Repair Processes in Multiple Sclerosis

Duffy

McCoy

2020

Cells

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Multiple sclerosis (MS) is an autoimmune disorder characterised by demyelination of central nervous system neurons with subsequent damage, cell death and disability. While mechanisms exist in the CNS to repair this damage, they are disrupted in MS and currently there are no treatments to address this deficit. In recent years, increasing attention has been paid to the influence of the small, non-coding RNA molecules, microRNAs (miRNAs), in autoimmune disorders, including MS. In this review, we examine the role of miRNAs in remyelination in the different cell types that contribute to MS. We focus on key miRNAs that have a central role in mediating the repair process, along with several more that play either secondary or inhibitory roles in one or more aspects. Finally, we consider the current state of miRNAs as therapeutic targets in MS, acknowledging current challenges and potential strategies to overcome them in developing effective novel therapeutics to enhance repair mechanisms in MS.

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Section: Contribution Of Mirnas To Remyelination In Cns Cellsmentioning

confidence: 99%

The Role of MicroRNAs in Repair Processes in Multiple Sclerosis

Duffy

McCoy

2020

Cells

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“…The higher occurrence of oxidative DNA damage and impaired repair compared to other CNS cell types, challenge the genomic stability of OPCs [ 51 , 123 , 124 ]. Furthermore, ROS can negatively impact DNA methylation, histone acetylation, and miRNA presence, which are all deemed necessary in OPC differentiation and especially relieving its blocking mechanisms [ 26 , 125 , 126 , 127 , 128 ]. Finally, the interplay between the metabolic functioning of mitochondria and ROS has been quite well established [ 129 ].…”

Section: Sphingosine-1-phosphate Receptors and Multiple Sclerosis mentioning

confidence: 99%

“…All the steps are accurately tuned by extrinsic and intrinsic factors, determining the correct timing of OPC proliferation, migration, and differentiation. Stimuli, including a diversity of extracellular signals, growth factors, transcription factors, and epigenetic modulators, play a key role in the process of myelin formation [ 24 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

“…OPCs exhibit a remarkably low antioxidant capacity compared to other cell types, as well as higher production of reactive oxygen species (ROS) [ 48 , 49 , 50 ]. Oxidative stress can be linked to the OPC differentiation block, since ROS are capable of compromising a variety of genetic, epigenetic, and metabolic mechanisms usually crucial for differentiation [ 26 , 47 , 51 ].…”

Section: Introductionmentioning

confidence: 99%

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Sphingosine-1-Phosphate Receptor Modulators and Oligodendroglial Cells: Beyond Immunomodulation

Roggeri

Schepers

Tiane

et al. 2020

IJMS

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Multiple sclerosis (MS) is an autoimmune inflammatory disease characterized by demyelination, axonal loss, and synaptic impairment in the central nervous system (CNS). The available therapies aim to reduce the severity of the pathology during the early inflammatory stages, but they are not effective in the chronic stage of the disease. In this phase, failure in endogenous remyelination is associated with the impairment of oligodendrocytes progenitor cells (OPCs) to migrate and differentiate into mature myelinating oligodendrocytes. Therefore, stimulating differentiation of OPCs into myelinating oligodendrocytes has become one of the main goals of new therapeutic approaches for MS. Different disease-modifying therapies targeting sphingosine-1-phosphate receptors (S1PRs) have been approved or are being developed to treat MS. Besides their immunomodulatory effects, growing evidence suggests that targeting S1PRs modulates mechanisms beyond immunomodulation, such as remyelination. In this context, this review focuses on the current understanding of S1PR modulators and their direct effect on OPCs and oligodendrocytes.

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“…Many of the TFs specifying myelinating cell lineages and/or controlling lineage maturation have been identified (5,(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). Further, chromatin remodeling and epigenetic changes associated with myelin gene expression have identified numerous features of the chromatin landscape in which such regulatory components operate (33)(34)(35)(36)(37)(38)(39)(40).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Regulators of theGolli/Myelin Basic ProteinLocus Integrate Additive and Stealth Activities

Bagheri

Friedman

Siminovitch

et al. 2020

Preprint

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Myelin is composed of plasma membrane spirally wrapped around axons and compacted into dense sheaths by myelin associated proteins. In the central nervous system (CNS), myelin is elaborated by neuroepithelial derived oligodendrocytes and in the peripheral nervous system (PNS) by neural crest derived Schwann cells.While some myelin proteins are unique to only one lineage, myelin basic protein (Mbp) is expressed in both.Overlapping the Mbp gene is Golli, a transcriptional unit that is expressed widely both within and beyond the nervous system. A super-enhancer domain within the Golli/Mbp locus contains multiple enhancers shown previously to drive reporter construct expression specifically in oligodendrocytes or Schwann cells. In order to determine the contribution of each enhancer to the Golli/Mbp expression program and examine if interactions among these enhancers occur, we derived mouse lines in which enhancers were deleted, either singly or in different combinations, and relative mRNA accumulation was measured at key stages of development.Although super-enhancers have been shown to facilitate interaction among their component enhancers, the enhancers investigated here demonstrated functions that were largely additive. However, enhancers demonstrating autonomous activity strictly in one cell lineage, when missing, were found to significantly reduce output in the other thus revealing cryptic "stealth" activity. Further, Golli accumulation in all cell types investigated was markedly and uniformly attenuated by the absence of a key oligodendrocyte enhancer. Our observations expose a novel level of enhancer interaction and are consistent with a model in which enhancermediated DNA looping underlies higher-order Golli/Mbp regulatory organization. AUTHOR SUMMARYThe control of transcription is mediated through regulatory sequences that engage in a lineage and developmentally contextual manner. The Golli/Mbp locus gives rise to several mRNAs and while Mbp mRNAs accumulate exclusively in the two glial cell types that elaborate myelin, Golli mRNAs accumulate in diverse cell types both within and beyond the nervous system. To determine how the different Golli/Mbp enhancers distribute their activities and to reveal if they operate as autonomous agents or have functionally significant interactions with each other we derived multiple enhancer knock-out lines. Comparing the developmental accumulation of Mbp and Golli mRNAs revealed that the autonomous targeting capacity of multiple enhancers accurately predicted their in-situ contributions. Also, they acted in a largely additive manner indicating significant individual autonomy that can be accounted for by a simple chromatin looping model. Unexpectedly, we also uncovered cryptic "stealth" activity emanating from these same enhancers in lineages where they show no autonomous targeting capacity thus providing new insight into the control of lineage specific gene expression.

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From OPC to Oligodendrocyte: An Epigenetic Journey

Cited by 87 publications

References 172 publications

The Role of MicroRNAs in Repair Processes in Multiple Sclerosis

The Role of MicroRNAs in Repair Processes in Multiple Sclerosis

Sphingosine-1-Phosphate Receptor Modulators and Oligodendroglial Cells: Beyond Immunomodulation

Transcriptional Regulators of theGolli/Myelin Basic ProteinLocus Integrate Additive and Stealth Activities

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