The epigenetic landscape of oligodendrocyte progenitors changes with time

Adult oligodendrocyte progenitors (aOPCs) share with their neonatal counterpart (nOPCs) 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, we define the unique transcriptome and histone marks of aOPCs. We describe the lower proliferative capacity and higher levels of expression of oligodendrocyte specific genes in aOPC compared to nOPC. We also identify greater levels of activating H4K8ac histone marks in aOPCs compared to nOPCs, and increased occupancy of this mark at chromatin locations corresponding to oligodendrocyte-specific transcription factors and lipid metabolism genes. Pharmacological inhibition of H4K8ac deposition reduces the levels of these transcripts in aOPCs, rendering their transcriptome more similar to nOPCs. The repressive H4K20me3 mark is also higher in aOPCs compared to nOPCs and pharmacological inhibition of its deposition results in increased levels of genes related to the mature oligodendrocyte state. Overall, this study identifies two histone marks which are important for the unique transcriptional identity of aOPCs. Overall design: Chromatin immunoprecipitaion with H4K8ac antibody followed by sequencing (ChIP-seq) on sorted neonatal oligodendrocyte progenitors (nOPCs) and adult OPCs (aOPCs) from PdgfraH2BEGFP mice.