miR-142-3p Regulates Cortical Oligodendrocyte Gene Co-expression Networks Associated with Tauopathy

Oligodendrocytes exist in a heterogenous state and are implicated in multiple neuropsychiatric diseases including dementia. Cortical oligodendrocytes are a glial population uniquely positioned to play a key role in neurodegeneration by synchronizing circuit connectivity but molecular pathways specific to this role are lacking. We utilized oligodendrocyte-specific translating ribosome affinity purification and RNA-seq (TRAP-seq) to transcriptionally profile adult mature oligodendrocytes from different regions of the central nervous system. Weighted gene co-expression network analysis (WGCNA) reveals distinct region-specific gene networks. Two of these mature myelinating oligodendrocyte gene networks uniquely define cortical oligodendrocytes and differentially regulate cortical myelination (M8) and synaptic signaling (M4). These two cortical oligodendrocyte gene networks are enriched for genes associated with dementia including MAPT and include multiple gene targets of the regulatory microRNA, miR-142-3p. Using a combination of TRAP-qPCR, miR-142-3p overexpression in vitro, and miR-142-null mice, we show that miR-142-3p negatively regulates cortical myelination. In rTg4510 tau-overexpressing mice, cortical myelination is compromised, and tau-mediated neurodegeneration is associated with gene co-expression networks that recapitulate both the M8 and M4 cortical oligodendrocyte gene networks identified from normal cortex. We further demonstrate overlapping gene networks in mature oligodendrocytes present in normal cortex, rTg4510 and miR-142-null mice, and existing datasets from human tauopathies to provide evidence for a critical role of miR-142-3p-regulated cortical myelination and oligodendrocyte-mediated synaptic signaling in neurodegeneration. Mutliple WGCNA of RNA-seq datasets少突胶质细胞（Oligodendrocytes）以异质性状态存在，且与包括痴呆在内的多种神经精神疾病密切相关。皮层少突胶质细胞作为一类独特的胶质细胞群，可通过同步神经环路连接在神经退行性变中发挥关键作用，但目前仍缺乏对应这一功能的特异性分子通路研究。我们采用少突胶质细胞特异性翻译核糖体亲和纯化联合RNA测序（translating ribosome affinity purification and RNA-seq, TRAP-seq）技术，对中枢神经系统不同区域的成年成熟少突胶质细胞开展转录组分析。通过加权基因共表达网络分析（Weighted gene co-expression network analysis, WGCNA），我们揭示了具有显著区域特异性的基因调控网络。其中两个髓鞘形成型成熟少突胶质细胞基因网络可特异性表征皮层少突胶质细胞，并分别调控皮层髓鞘形成（M8）与突触信号传递（M4）。这两个皮层少突胶质细胞基因网络富含与痴呆相关的基因（包括MAPT基因），同时包含调控型微小RNA miR-142-3p的多个靶基因。我们联合运用TRAP-qPCR、体外过表达miR-142-3p以及miR-142基因敲除小鼠模型，证实miR-142-3p可负向调控皮层髓鞘形成。在rTg4510 tau过表达小鼠中，皮层髓鞘形成出现受损，且tau介导的神经退行性变与重现正常皮层来源的M8及M4皮层少突胶质细胞基因网络的共表达基因网络存在关联。我们进一步证实，正常皮层、rTg4510 tau过表达小鼠及miR-142基因敲除小鼠的成熟少突胶质细胞中存在重叠的基因调控网络，并结合人类tau蛋白病的现有数据集，为miR-142-3p调控的皮层髓鞘形成以及少突胶质细胞介导的突触信号传递在神经退行性变中的关键作用提供了实验证据。本研究针对多套RNA测序数据集开展了WGCNA分析。