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. Chromatin immunoprecipitaion with H4K8ac antibody followed by sequencing (ChIP-seq) on sorted neonatal oligodendrocyte progenitors (nOPCs) and adult OPCs (aOPCs) from PdgfrαH2BEGFP mice.

成年少突胶质细胞前体细胞（Adult oligodendrocyte progenitors, aOPCs）与新生期少突胶质细胞前体细胞（neonatal oligodendrocyte progenitors, nOPCs）均具备分化为具有髓鞘形成能力的少突胶质细胞的潜能，但二者同时具备各自独特的功能特征。本研究旨在解析这两类细胞群体内在差异背后的分子机制。研究团队通过RNA测序（RNA-sequencing）与无偏倚组蛋白蛋白质组学分析，明确了aOPCs独特的转录组与组蛋白修饰标记特征。研究发现，相较于nOPCs，aOPCs的增殖能力更低，且少突胶质细胞特异性基因的表达水平更高。此外，研究人员还鉴定到aOPCs中活化型H4K8ac组蛋白修饰标记的水平显著高于nOPCs，且该修饰在对应少突胶质细胞特异性转录因子与脂质代谢基因的染色质位点上的富集度同样更高。对H4K8ac的沉积进行药物抑制后，aOPCs中上述基因的转录水平出现下调，使其转录组特征更接近nOPCs。抑制型H4K20me3修饰标记在aOPCs中的水平同样高于nOPCs，对该修饰的沉积进行药物抑制则会使成熟少突胶质细胞相关基因的表达水平升高。综上，本研究鉴定出两种对aOPCs独特转录身份具有重要调控作用的组蛋白修饰标记。本研究的实验方法为：从PdgfrαH2BEGFP小鼠中分选新生期与成年少突胶质细胞前体细胞，采用基于H4K8ac抗体的染色质免疫共沉淀结合测序（ChIP-seq）开展检测。