| 1. |
- Marques, Sueli, et al.
(författare)
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Transcriptional Convergence of Oligodendrocyte Lineage Progenitors during Development
- 2018
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Ingår i: Developmental Cell. - : Elsevier BV. - 1878-1551 .- 1534-5807. ; 46:4, s. 504-517
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Tidskriftsartikel (refereegranskat)abstract
- Pdgfra+ oligodendrocyte precursor cells (OPCs) arise in distinct specification waves during embryogenesis in the central nervous system (CNS). It is unclear whether there is a correlation between these waves and different oligodendrocyte (OL) states at adult stages. Here, we present bulk and single-cell transcriptomics resources providing insights on how transitions between these states occur. We found that post-natal OPCs from brain and spinal cord present similar transcriptional signatures. Moreover, post-natal OPC progeny of E13.5 Pdgfra+ cells present electrophysiological and transcriptional profiles similar to OPCs derived from subsequent specification waves, indicating that Pdgfra+ pre-OPCs rewire their transcriptional network during development. Single-cell RNA-seq and lineage tracing indicates that a subset of E13.5 Pdgfra+ cells originates cells of the pericyte lineage. Thus, our results indicate that embryonic Pdgfra+ cells in the CNS give rise to distinct post-natal cell lineages, including OPCs with convergent transcriptional profiles in different CNS regions.
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| 2. |
- Meijer, Mandy, et al.
(författare)
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Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosis susceptibility
- 2022
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Ingår i: Neuron. - : Elsevier. - 0896-6273 .- 1097-4199. ; 110:7, s. 1193-1210
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is characterized by a targeted attack on oligodendroglia (OLG) and myelin by immune cells, which are thought to be the main drivers of MS susceptibility. We found that immune genes exhibit a primed chromatin state in single mouse and human OLG in a non-disease context, compatible with transitions to immune-competent states in MS. We identified BACH1 and STAT1 as transcription factors involved in immune gene regulation in oligodendrocyte precursor cells (OPCs). A subset of immune genes presents bivalency of H3K4me3/H3K27me3 in OPCs, with Polycomb inhibition leading to their increased activation upon interferon gamma (IFN-g) treatment. Some MS susceptibility single-nucleotide polymorphisms (SNPs) overlap with these regulatory regions in mouse and human OLG. Treatment of mouse OPCs with IFN-g leads to chromatin architecture remodeling at these loci and altered expression of interacting genes. Thus, the susceptibility for MS may involve OLG, which therefore constitutes novel targets for immunological based therapies for MS.
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| 3. |
- Meijer, Mandy
(författare)
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Gene regulatory mechanisms in the oligodendrocyte lineage in development and disease
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Oligodendrocytes are the myelinating cells of the central nervous system (CNS). They contribute to the neuronal network through the insulation of neuronal axons, facilitating communication between neurons and providing metabolic support. In multiple sclerosis (MS), oligodendrocytes are attacked by the immune system leading to a wide variety of symptoms. Remyelination is necessary for functional recovery, which can occur through the recruitment and differentiation of oligodendrocyte precursor cells (OPCs) that reside in the adult CNS. During development and in disease, oligodendrocytes and OPCs (oligodendroglia) undergo significant changes at the transcriptional level. However, the genomes remain the same within these cells, so how do these transcriptional changes occur? In this thesis, we investigate gene regulatory mechanisms in the oligodendrocyte lineage in development and disease. In Paper I we investigate the role of citrullination in the differentiation of oligodendrocytes. We identify peptidylarginine deiminase 2 (PAD2) as the major citrullinating enzyme in oligodendrocytes, promoting oligodendrocyte differentiation through the upregulation of myelin genes. Interestingly, the main targets of PAD2 are proteins involved in transcriptional and posttranscriptional regulation. Other PAD2 targets are myelin proteins, which might explain the motor and cognitive deficits and the decrease in myelinated axons we observe upon loss of PAD2. In Paper II we characterize how the oligodendrocyte lineage is affected in disease, using single-cell transcriptomics in the MS mouse model experimental autoimmune encephalomyelitis (EAE). Oligodendroglia in EAE mice show an increase in immune pathway genes including major histocompatibility complex (MHC) class-I and -II genes involved in antigen processing and presentation. Furthermore, OPCs stimulated with interferon-gamma interact with and activate CD4 positive T cells. Thus, oligodendroglia might have a more active role in mediating the inflammatory response in MS than previously thought. In Paper III we investigate how oligodendroglia transition to the immune state, using single- cell ATAC-seq in EAE mice. We find that immune genes are primed and increase their expression in an inflammatory environment through changes in the histone modification landscape, in chromatin interactions, and in transcription factor binding. Overall, we identify gene regulatory mechanisms of the immune program in oligodendroglia that could be possible therapeutic targets for MS. In Paper IV we develop an extension of the method genome architecture mapping (immunoGAM), which we apply to study genome-wide chromatin interactions in intact brain tissue. We find interactions and mechanisms that are specific for different brain cell types. Long neuronal genes that are active, often show decondensation or ‘melting’. Furthermore, topologically associating domains and A/B compartments reorganize extensively upon differentiation, and cell type-specific interactions form mediated by specific transcription factor pairs. To conclude, this thesis examines different layers of gene regulation including chromatin accessibility, histone modifications, genome interactions, and transcription factor binding. More specifically, we investigate how these different layers are involved in the transitioning of oligodendroglia during differentiation or to disease states. The findings in this thesis will hopefully contribute to the development of improved treatment strategies for MS.
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| 4. |
- van Bruggen, David, et al.
(författare)
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Developmental landscape of human forebrain at a single-cell level identifies early waves of oligodendrogenesis
- 2022
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Ingår i: Developmental Cell. - : Elsevier BV. - 1534-5807 .- 1878-1551. ; 57:11, s. 1421-1436, 1421-1436.e1-e5
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Tidskriftsartikel (refereegranskat)abstract
- Oligodendrogenesis in the human central nervous system has been observed mainly at the second trimester of gestation, a much later developmental stage compared to oligodendrogenesis in mice. Here, we characterize the transcriptomic neural diversity in the human forebrain at post-conception weeks (PCW) 8–10. Using single-cell RNA sequencing, we find evidence of the emergence of a first wave of oligodendrocyte lineage cells as early as PCW 8, which we also confirm at the epigenomic level through the use of single-cell ATAC-seq. Using regulatory network inference, we predict key transcriptional events leading to the specification of oligodendrocyte precursor cells (OPCs). Moreover, by profiling the spatial expression of 50 key genes through the use of in situ sequencing (ISS), we identify regions in the human ventral fetal forebrain where oligodendrogenesis first occurs. Our results indicate evolutionary conservation of the first wave of oligodendrogenesis between mice and humans and describe regulatory mechanisms involved in human OPC specification.
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