Emerging roles of RNA modifications in normal development and congenital craniofacial malformations

RNA modifications represent a pivotal epitranscriptomic layer modulating gene expression beyond the classic central dogma. Increasing studies have revealed their essential roles in orchestrating mammalian development and contributing to congenital disorders. In this review, we focus on seven well-characterized RNA modifications, including N⁶-methyladenosine(m⁶A), N¹-methyladenosine(m¹A), 5-methylcytosine (m⁵C), N⁴-acetylcytosine (ac⁴C), N⁷-methylguanosine (m⁷G), pseudouridine (Ψ), and adenosine-to-inosine (A-to-I) editing, and briefly introduce emerging marks like N¹-methylguanosine at position 9 (m¹G9) and N²-methylguanosine (m²G). We first summarize their distribution patterns and regulatory mechanisms. Then, we examine their stage-specific functions during early embryogenesis, from fertilization to post-implantation. Further, we integrate current evidence linking RNA modifications to craniofacial development, categorized into system-associated and localized craniofacial malformations. Special attention is given to their crosstalk with chromatin dynamics and neural crest cell plasticity. Finally, we discuss their potential as environmental sensors and therapeutic targets, emphasizing the need to decode their roles in craniofacial morphogenesis. Understanding the mechanistic roles of RNA modifications in craniofacial morphogenesis opens new avenues for uncovering disease etiology, discovering diagnostic biomarkers, and designing targeted therapies. A structured literature review using PubMed and Web of Science was performed, using keywords like RNA modifications, craniofacial malformations and epitranscriptomics.

RNA修饰是一类关键的表观转录组调控层，可在经典中心法则之外调控基因表达。日益增多的研究揭示了其在调控哺乳动物发育、参与先天性疾病发生过程中的核心作用。本综述聚焦七种已被充分表征的RNA修饰，包括N⁶-甲基腺嘌呤（N⁶-methyladenosine, m⁶A）、N¹-甲基腺嘌呤（N¹-methyladenosine, m¹A）、5-甲基胞嘧啶（5-methylcytosine, m⁵C）、N⁴-乙酰胞嘧啶（N⁴-acetylcytosine, ac⁴C）、N⁷-甲基鸟苷（N⁷-methylguanosine, m⁷G）、假尿苷（pseudouridine, Ψ）以及腺苷-肌苷（A-to-I）编辑，并简要介绍了第9位N¹-甲基鸟苷（m¹G9）与N²-甲基鸟苷（m²G）等新兴修饰标记。我们首先综述了它们的分布模式与调控机制；随后探讨了其在从受精至植入后的早期胚胎发生过程中发挥的阶段特异性功能。进一步，我们整合了当前将RNA修饰与颅面发育相关联的现有证据，并将其划分为系统性关联型颅面畸形与局灶性颅面畸形两类。本研究特别关注了RNA修饰与染色质动态变化、神经嵴细胞可塑性之间的交互作用。最后，我们讨论了RNA修饰作为环境传感器与治疗靶点的潜在价值，并强调了解码其在颅面形态发生中作用的必要性。阐明RNA修饰在颅面形态发生中的机制性作用，可为揭示疾病病因、发掘诊断生物标志物以及设计靶向治疗方案开辟全新路径。本综述通过PubMed与Web of Science数据库开展系统性文献调研，检索关键词涵盖RNA修饰、颅面畸形及表观转录组学。