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.