Oligodendrocyte differentiation alters tRNA modifications and codon-dependent mRNA decay [RiboSeq]. 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）是介导神经元髓鞘形成的特化细胞。已知当多种转运RNA（transfer RNA，tRNA）代谢基因发生突变时，会引发与少突胶质细胞相关的脑白质营养不良（Leukodystrophies）及髓鞘形成低下（hypomyelination）。尽管具体机制尚未明确，但少突胶质细胞可能对tRNA生物学功能紊乱具有高度敏感性。本研究对小鼠少突胶质细胞谱系的tRNA转录组展开分析，以期阐明该类人类疾病的分子基础。研究发现，少突胶质细胞内反密码子区域或其邻近区域的特定tRNA存在修饰低下现象。这种低修饰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表达。此外，我们观察到tRNA低修饰与tRNA解码潜能之间存在伴随关联：在少突胶质细胞中可观察到密码子最优性介导的mRNA降解及核糖体转运过程出现细胞特异性改变。本研究结果揭示，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代谢再次受到外界损伤时，该调控轴的异常将成为疾病的发病机制。
整体实验设计：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（QuantM-seq），每组均设置2个生物学重复。