Stage-specific requirement for METTL3-dependent m(6)A modification during dental pulp stem cell differentiation.
Stage-specific requirement for METTL3-dependent m(6)A modification during dental pulp stem cell differentiation.
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牙髓干细胞分化过程中 METTL3 依赖性 m6A 修饰的阶段特定要求
DOI：
10.1186/s12967-022-03814-9
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发表时间：
2022-12-16
影响因子：
7.4
通讯作者：
Shao, Longquan
中科院分区：
文献类型：
--
作者：
Luo, Haiyun;Liu, Wenjing;Zhou, Yachuan;Zhang, Yanli;Wu, Junrong;Wang, Ruolan;Shao, Longquan
N6-甲基腺苷（m6 A）是真核生物信使RNA中最常见的表观遗传修饰，在细胞命运转变中起着关键作用。然而，m6 A标记如何在功能上影响协调干细胞分化的转录级联仍有待阐明。本研究旨在探讨m6 A甲基化在牙髓干细胞分化中的生物学功能及其机制。利用m6 A RNA免疫沉淀测序来评估DPSC分化期间的m6 A-mRNA景观。将DPSC异位移植到免疫缺陷小鼠体内以验证体外结果。结合RNA测序和m6 A RNA免疫沉淀测序来鉴定候选靶标。RNA免疫沉淀和RNA/蛋白质稳定性的Noggin（NOG）进行了评价。用3′-RACE和poly（A）尾长测定法检测poly（A）尾的变化。我们描述了DPSC矿化过程中m6 A-mRNA的动态景观，3′非翻译区（UTR）的富集程度增加。甲基转移酶样3（Methyltransferase-like 3，简称M3）被鉴定为关键的m6 A参与者，并且M3敲低破坏了功能性DPSC分化。此外，胃L3过表达增强DPSC矿化。增加m6 A在3′ UTR的沉积限制了NOG的表达，这是DPSC矿化所必需的。这种阶段特异性m6 A甲基化和NOG的不稳定化仅在分化的DPSC中被胃L3敲低抑制。此外，在分化阶段，胃L3通过缩短poly（A）尾长来促进m6 A标记的NOG的降解。我们的研究结果解决了动态m6 A信号在DPSC分化的时间控制中的重要作用，并为基于干细胞的治疗中的表观转录机制提供了新的见解。在线版本包含补充材料，可通过10.1186/s12967-022-03814-9获得。
N6-methyladenosine (m6A) is the most prevalent epigenetic modification in eukaryotic messenger RNAs and plays a critical role in cell fate transition. However, it remains to be elucidated how m6A marks functionally impact the transcriptional cascades that orchestrate stem cell differentiation. The present study focuses on the biological function and mechanism of m6A methylation in dental pulp stem cell (DPSC) differentiation. m6A RNA immunoprecipitation sequencing was utilized to assess the m6A-mRNA landscape during DPSC differentiation. Ectopic transplantation of DPSCs in immunodeficient mice was conducted to verify the in vitro findings. RNA sequencing and m6A RNA immunoprecipitation sequencing were combined to identify the candidate targets. RNA immunoprecipitation and RNA/protein stability of Noggin (NOG) were evaluated. The alteration in poly(A) tail was measured by 3′-RACE and poly(A) tail length assays. We characterized a dynamic m6A-mRNA landscape during DPSC mineralization with increasing enrichment in the 3′ untranslated region (UTR). Methyltransferase-like 3 (METTL3) was identified as the key m6A player, and METTL3 knockdown disrupted functional DPSC differentiation. Moreover, METTL3 overexpression enhanced DPSC mineralization. Increasing m6A deposition in the 3′ UTR restricted NOG expression, which is required for DPSC mineralization. This stage-specific m6A methylation and destabilization of NOG was suppressed by METTL3 knockdown only in differentiated DPSCs. Furthermore, METTL3 promotes the degradation of m6A-tagged NOG by shortening the poly(A) tail length in the differentiated stage. Our results address an essential role of dynamic m6A signaling in the temporal control of DPSC differentiation and provide new insight into epitranscriptomic mechanisms in stem cell-based therapy. The online version contains supplementary material available at 10.1186/s12967-022-03814-9.
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