Zhang Xinye, Zhou Linfang, Tian Cheng, Tao Huangheng
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China.
Xiamen Key Laboratory of Stomatological Disease Diagnosis and Treatment, Stomatological Hospital of Xiamen Medical College, Xiamen, China.
Front Mol Biosci. 2025 Aug 4;12:1599487. doi: 10.3389/fmolb.2025.1599487. eCollection 2025.
N-methyladenosine (mA), an abundant internal RNA modification in eukaryotes, serves as a dynamic post-transcriptional regulator of gene expression by influencing RNA splicing, stability, translation, and decay. This reversible epitranscriptomic mechanism, which is mediated by methyltransferase (writers), demethylase (erasers), and mA-binding proteins (readers), is pivotal in diverse biological contexts. Among mA erasers, alkylation repair homolog protein 5 (ALKBH5), an Fe(II)/α-ketoglutarate-dependent dioxygenase, is the second to be discovered and one of the most significant demethylases. Mounting evidence underscores ALKBH5's role in modulating developmental programming, where it coordinates processes such as lineage specification, organogenesis, and tissue homeostasis. This review systematically deciphers the multifaceted contributions of ALKBH5-mediated mA demethylation to developmental biology. We synthesize recent advances elucidating how ALKBH5-driven mA erasure dynamically regulates transcriptomic rewiring during embryogenesis, reproductive development, cardiac development, central nervous system development, immune system development, pancreatic organogenesis, osteogenic/odontogenic differentiation, adipogenesis, and angiogenesis. These revelations not only deepen our understanding of epitranscriptomic regulation in ontogeny but also illuminate therapeutic avenues for developmental anomalies and regenerative medicine.
N-甲基腺苷（mA）是真核生物中一种丰富的内部RNA修饰，通过影响RNA剪接、稳定性、翻译和降解，作为基因表达的动态转录后调节因子。这种由甲基转移酶（写入器）、去甲基化酶（擦除器）和mA结合蛋白（读取器）介导的可逆表观转录组学机制，在多种生物学背景中至关重要。在mA擦除器中，烷基化修复同源蛋白5（ALKBH5）是一种依赖于Fe（II）/α-酮戊二酸的双加氧酶，是第二个被发现且最重要的去甲基化酶之一。越来越多的证据强调了ALKBH5在调节发育程序中的作用，它在其中协调谱系特化、器官发生和组织稳态等过程。本综述系统地解读了ALKBH5介导的mA去甲基化对发育生物学的多方面贡献。我们综合了最近的研究进展，阐明了在胚胎发生、生殖发育、心脏发育、中枢神经系统发育、免疫系统发育、胰腺器官发生、成骨/成牙分化、脂肪生成和血管生成过程中，ALKBH5驱动的mA擦除如何动态调节转录组重排。这些发现不仅加深了我们对个体发育中表观转录组调控的理解，也为发育异常和再生医学指明了治疗途径。
