Oligodendrocyte differentiation alters tRNA modifications and codon-dependent mRNA decay [RiboSeq]

Oligodendrocytes are specialized cells that confer neuronal myelination. Leukodystrophies associated with oligodendrocyte and hypomyelination are known to result when a number of tRNA metabolism genes are mutated. Thus, for unknown reasons, oligodendrocytes may be hypersensitive to perturbations in tRNA biology. In this study, we survey the tRNA transcriptome in the murine oligodendrocytes cell lineage in an effort to understanding the molecular underpinning for human disease. We find that specific tRNAs are hypomodified in oligodendrocytes within or near the anticodon. This hypomodified state may be the result of differential expression of key modification enzymes during oligodendrocyte differentiation. Moreover, we observe a concomitant relationship between tRNA hypomodification and tRNA decoding potential; observing oligodendrocyte specific alterations in codon optimality-mediated mRNA decay and ribosome transit. Our results reveal that oligodendrocytes naturally maintain a delicate, hypersensitized tRNA/mRNA axis. We suggest this axis underlies disease etiology when further insult to tRNA metabolism is introduced. Overall design: Ribosome profiling and associated RNA-Seq data (QuantM-seq) of murine Oligodendrocyte Progenitor Cells (OPCs) (2 replicates each) and Oligodendrocytes (OLs) (2 replicates each)

少突胶质细胞（Oligodendrocytes）是一类介导神经元髓鞘形成的特化细胞。现已证实，当多个tRNA代谢相关基因发生突变时，可引发与少突胶质细胞功能异常及髓鞘形成低下相关的脑白质营养不良（Leukodystrophies）。因此，尽管具体分子机制尚不明确，少突胶质细胞可能对tRNA生物学功能的紊乱具有高度易感性。本研究中，我们对小鼠（murine）少突胶质细胞谱系的tRNA转录组（tRNA transcriptome）进行全景分析，以期阐明此类人类疾病的分子基础。我们发现，少突胶质细胞内部分特定tRNA的反密码子（anticodon）区域及其邻近位点存在修饰低下现象。该修饰低下状态可能源于少突胶质细胞分化过程中关键修饰酶的差异化表达。此外，我们还观察到tRNA修饰低下与tRNA解码潜能之间存在显著伴随关联；同时发现少突胶质细胞中存在密码子最优性介导的mRNA降解及核糖体转运过程的细胞特异性改变。本研究结果表明，少突胶质细胞天然维持着一套精细且高度敏感的tRNA/mRNA调控轴。我们推测，当tRNA代谢再次受到额外损伤时，这套调控轴的异常即为疾病的发病基础。实验设计：针对小鼠少突胶质前体细胞（Oligodendrocyte Progenitor Cells, OPCs）及少突胶质细胞（Oligodendrocytes, OLs）开展核糖体谱分析（Ribosome profiling）及配套RNA测序（RNA-Seq, QuantM-seq），两类样本各设置2次生物学重复。