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RNA-sequencing of mouse knockout models for Cnp, Plp1, and Ugt8 in the frontal cortex and cerebellum

ABSTRACT: Oligodendrocytes (OLs) and myelin are critical for normal brain function and they have been implicated in neurodegeneration. Human neuroimaging studies have demonstrated that alterations in axons and myelin occur early in Alzheimer’s Disease (AD) course. However, the molecular mechanism underlying the role of OLs in AD remains largely unknown. In this study, we systematically interrogated OL-enriched gene networks constructed from large-scale genomic, transcriptomic, and proteomic data in human AD postmortem brain samples. These robust OL networks were highly enriched for genes associated with AD risk variants, including BIN1. We corroborated the structure of the AD OL coexpression and gene-gene interaction networks through ablation of genes identified as key drivers of the networks, including UGT8, CNP, MYRF, PLP1, NPC1, and NDGR1. Perturbations of these key drivers not only caused dysregulation in their associated network neighborhoods, but also mimicked pathways of gene expression dysregulation seen in human AD postmortem brain samples. In particular, the OL subnetwork controlled by the AD risk gene PSEN1 was strongly dysregulated in AD, suggesting a potential role of PSEN1 in disrupting the myelination pathway towards the onset of AD. In summary, this study built and systematically validated the first comprehensive molecular blueprint of OL dysregulation in AD, and identified key OL- and myelination-related genes and networks as potential candidate targets for the future development of AD therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE80437 | GEO | 2018/02/23

REPOSITORIES: GEO

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Project description:Myelin destruction and oligodendrocyte (OL) death consequent to metabolic stress is a feature of CNS disorders across the age spectrum. Using cells derived from surgically resected tissue, we demonstrate that young (<age 5) pediatric-aged sample OLs are more resistant to in-vitro metabolic injury than fetal O4+ progenitor cells, but more susceptible to cell death and apoptosis than adult-derived OLs. Pediatric but not adult OLs show measurable levels of TUNEL+ cells, a feature of the fetal cell response. The ratio of anti- versus pro-apoptotic BCL-2 family genes are increased in adult versus pediatric (<age 5) mature OLs and in more mature OL lineage cells. Lysosomal gene expression was increased in adult and pediatric compared to fetal OL lineage cells. Cell death of OLs was increased by inhibiting pro-apoptotic BCL-2 gene and autophagy activity. These distinct age-related injury responses should be considered in designing therapies aimed at reducing myelin injury.

2020-12-31 | GSE160811 | GEO

2020-12-31 | GSE160810 | GEO

Olig2 ablation in immature oligodendrocytes does not enhance CNS myelination and remyelination

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2022-11-23 | GSE194258 | GEO

Gsta4 restricts apoptosis in differentiating adult oligodendrocytes via Fas/Casp8/Bid-axis during homeostasis and remyelination

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2020-07-23 | GSE154922 | GEO

Transcription factor-dependent differences in cluster composition and transition states of oligodendrocyte differentiation from human stem cells

Project description:Oligodendrocytes (OLs) are critical for myelination and are implicated in several brain disorders. Directed differentiation of human induced OLs (iOLs) from pluripotent stem cells can be achieved by forced expression of different combinations of the transcription factors SOX10 (S), OLIG2 (O) and NKX6.2 (N). Here, we applied quantitative image analysis and single-cell transcriptomics to compare different transcription factor combinations for their efficacy towards robust OL lineage conversion. Compared with S alone, the combination of SON significantly increases the number of myelin basic protein-positive iOLs and generates iOLs with a more complex morphology and higher expression levels of myelin-marker genes . The analysis of RNA velocity of individual cells reveals that S generates a population of volatile oligodendrocyte-precursor cells (OPCs) that appear to be more immature than those generated by SON and to display distinct molecular properties. Our analysis suggests that protocols for generating iOPCs or iOLs should be chosen depending on the intended application.

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Identification of genome-wide targets of Olig2 in the adult mouse spinal cord using ChIP-Seq

Project description:Olig2 is a crucial factor in the specification and differentiation of oligodendrocyte precursor cells that give rise to mature, myelin-producing OLs in the developing and postnatal CNS; however, its role in adulthood is less well understood. To investigate the role Olig2 plays in regulating gene expression in the adult oligodendrocyte lineage in a physiologically-relevant context, we performed chromatin immunoprecipitation followed by next generation sequencing analysis using whole spinal cord tissue harvested from adult mice. We found that many of the Olig2-bound sites were associated with genes with biological processes corresponding to myelination and ensheathment, as well as cell cycle and cytoskeletal regulation, suggesting Olig2 continues to play a critical role in processes related to OL differentiation and myelination well into adulthood.

2017-10-20 | GSE103324 | GEO

Transient regulation of focal adhesion via Tensin3 is required for nascent oligodendrocyte differentiation [RNA-seq]

Project description:The differentiation of oligodendroglia from oligodendrocyte precursor cells (OPCs) to complex and extensive myelinating oligodendrocytes (OLs) is a multistep process that involves largescale morphological changes with significant strain on the cytoskeleton. While key chromatin and transcriptional regulators of differentiation have been identified, their target genes responsible for the morphological changes occurring during OL myelination are still largely unknown. Here, we show that the regulator of focal adhesion, Tensin3 (Tns3), is a direct target gene of Olig2, Chd7, and Chd8, transcriptional regulators of OL differentiation. Tns3 is transiently upregulated and localized to cell processes of immature OLs, together with integrin-b1, a key mediator of survival at this transient stage. Constitutive Tns3 loss-of-function leads to reduced viability in mouse and humans, with surviving knockout mice still expressing Tns3 in oligodendroglia. Acute deletion of Tns3 in vivo, either in postnatal neural stem cells (NSCs) or in OPCs, leads to a two-fold reduction in OL numbers. We find that the transient upregulation of Tns3 is required to protect differentiating OPCs and immature OLs from cell death by preventing the upregulation of p53, a key regulator of apoptosis. Altogether, our findings reveal a specific time window during which transcriptional upregulation of Tns3 in immature OLs is required for OL differentiation likely by mediating integrin-b1 survival signaling to the actin cytoskeleton as OL undergo the large morphological changes required for their terminal differentiation.

2022-09-01 | GSE203294 | GEO

Transient regulation of focal adhesion via Tensin3 is required for nascent oligodendrocyte differentiation [ChIP-seq]

2022-09-01 | GSE203293 | GEO

scRNAseq of co-culture of primary human oligodendrocytes and IL-23 polarized human CD4 T cells in direct contact (contact) versus separated by a porous membrane (insert, no contact)

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2022-02-28 | GSE196953 | GEO

*Possible corruption in count data files-update in progress* Disease-specific oligodendrocyte lineage cells express immunoprotective and adaptive immunity genes in multiple sclerosis

Project description:Single-cell RNA-seq of a mouse model of MS uncovers new oligodendrocyte populations, putative disease markers and suggests new mechanisms underlying the pathogenesis of disease. In Multiple Sclerosis (MS), oligodendrocytes (OLs) are damaged during an immune system attack targeting myelin. It remains unclear how different OL lineage cells respond to inflammatory autoimmune demyelination in MS. We performed single-cell transcriptomics analysis of OL lineage cells from the spinal cord of mice induced with experimental autoimmune encephalomyelitis (EAE), which mimics certain aspects of MS. We found unique OLs and OL precursor cells (OPCs) in EAE, including populations expressing genes involved in antigen processing and presentation via major histocompatibility complex (MHC) Class I and II, but also in immunoprotection. We further uncovered several genes specifically alternatively spliced in OL lineage cells in EAE, including Mbp, Mobp and Pdgfa. Strikingly, we identified a substantial number of genes known to be susceptibility genes for MS, so far mainly associated with immune cells in the context of this disease, to be expressed in the OL lineage cells. Finally, we found that disease-specific oligodendroglia are present in human MS brains. Our results suggest that OL and OPCs are not passive targets but instead active immunomodulators in MS. The disease-specific OL lineage cells, for which we identify several biomarkers, may represent novel direct targets for immunomodulatory therapeutic approaches in MS.

2018-08-25 | GSE113973 | GEO

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