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

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.