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RNA-seq of O4+ oligodendrocyte progenitors isolated from P5 and P60 mice

ABSTRACT: Adult oligodendrocyte progenitors (aOPCs) share with their neonatal counterpart (nOPC) the ability to give rise to myelinating oligodendrocytes, but they also display unique functional features. This study addresses the molecular mechanisms underlying the intrinsic differences between these two populations. Using RNA-sequencing and unbiased histone proteomics analysis performed on PDGFRa+ OPCs sorted from a reporter mouse, we define the unique transcriptome and histone marks of aOPCs. We describe the higher levels of genes related to lipid metabolism and myelin sheath, and lower expression of genes related to cycle and proliferation in aOPCs compared to nOPCs. We also identify greater levels of activating H4K8ac and repressive H4K20me3 histone marks in aOPCs compared to nOPCs, and increased occupancy of H4K8ac mark at chromatin locations corresponding to oligodendrocyte-specific genes. Pharmacological inhibition of histone acetylation in neonatal O4+OPCs (nO4+OPCs) and adult O4+OPCs (aO4+OPCs) followed by RNA-sequencing showed a moderate change in the transcriptome of these cells resulting in the decrease of proliferation capacity in aO4+OPCs but not nO4+OPCs. Pharmacological inhibition of H4K20me3 mark was not sufficient to change the transcriptome or functional properties of nO4+OPCs and aO4+OPC. Overall, this study identifies histone acetylation as key in regulating the proliferation of aO4+OPCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE263808 | GEO | 2024/08/01

REPOSITORIES: GEO

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Project description:In multiple sclerosis (MS) and experimental models of demyelination, myelin repair is mostly achieved by oligodendrocyte precursor cells (OPCs). To gain insight into the biological specificity of these adult precursors, in the perspective to better understand why remyelination often fails in MS, we performed a micro-array analysis on purified populations of murine OPCs and oligodendrocytes. We demonstrated that, in a control environment, M-bM-^@M-^\quiescentM-bM-^@M-^] adult OPCs are more mature than neonatal OPCs, with a mRNA profile closer to oligodendrocytes. However, when demyelination occurs, adult OPCs revert to an immature gene expression profile, acquiring higher migration and faster differentiation capacities. Among the many genes differentially regulated by these M-bM-^@M-^\activatedM-bM-^@M-^] adult OPCs, genes of the innate immune response, IL1M-NM-2 and CCL2 were strongly upregulated after demyelination, with increased protein expression in experimental demyelinating lesions and within MS plaques. We first showed in vitro that both IL1M-NM-2 and CCL2 M-bM-^@M-^\accountM-bM-^@M-^] for increased migration capacities of adult OPCs, an effect that is suppressed by corresponding receptor blockade. Focusing on Ccl2, we then demonstrated that lentiviral over-expression of Ccl2 increases motility of M-bM-^@M-^\quiescentM-bM-^@M-^] adult OPCs, which become as mobile as M-bM-^@M-^\activatedM-bM-^@M-^] adult OPCs. This in vitro gain of function was further confirmed in vivo, by showing an increased migration of grafted CG4 oligodendroglial cells over-expressing-Ccl2. These results, demonstrating that M-bM-^@M-^\activatedM-bM-^@M-^] adult OPCs upregulate immune cues favouring their migration, open new perspective of demyelination-induced immune-glial interactions, which might influence both oligodendroglial and inflammatory cells, therefore play a key role in lesion fate in multiple sclerosis. In this study, we loaded purified population of progenitors of oligodendrocytes (OPCs) (from neonatal, 2-month-old, 2-month-old and cuprizone-treated brains) and of mature oligodendrocytes (OLs) (2-month-old brains) and compared their gene expression. We compared gene expression of neonatal OPCs, adult OPCs, adult OLs and adult OPCs from control conditions and from demyelinating conditions, using 3 to 4 independant replicates in each group.

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RNA-seq of O4+ oligodendrocyte progenitors isolated from P5 and P60 mice

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