# Epigenetic Signatures of Dental Stem Cells: Insights into DNA Methylation and Noncoding RNAs
## 1 Introduction  
Tooth development, or odontogenesis, is a highly regulated biological process driven by reciprocal interactions between epithelial and mesenchymal tissues. These interactions are mediated through molecular signaling pathways, including BMP, Wnt, SHH, and FGF, which control cell proliferation, differentiation, and morphogenesis [1]. A detailed understanding of these pathways is essential not only for elucidating normal craniofacial development but also for advancing regenerative strategies in dentistry.  
In recent years, mesenchymal stem/stromal cells (MSCs) derived from dental tissues have emerged as valuable tools in tissue engineering. These cells, most notably dental pulp stem cells (DPSCs), periodontal ligament stem cells (PDLSCs), and dental follicle progenitor cells (DFPCs), exhibit the hallmarks of MSCs, including clonogenicity, multilineage differentiation, and immunomododulatory properties. As postnatal derivatives of neural crest cells, these stem cell populations are uniquely adapted to regenerate mineralized and soft tissues in the oral cavity [2; 3].  
Each of these odontogenic stem cell types displays distinct biological characteristics reflective of their developmental origin and niche [4; 5]. DPSCs are particularly effective in dentin-pulp regeneration; PDLSCs demonstrate robust osteogenic and tenogenic differentiation; and DEFPCs serve as progenitors for multiple periodontal structures. The accessibility and regenerative potential of these cell lines make them attractive candidates for clinical translation [6]. However, their differential performance in regenerative assays suggests that deeper molecular distinctions underlie their phenotypic variability. Among the mechanisms contributing to these functional differences, epigenetic regulation, particularly DNA methylation, plays a central role [7]. DNA methylation serves as a heritable but reversible regulatory mark that influences gene expression without altering the genetic code. In stem cells, DNA methylation is critical for maintaining multipotency and directing lineage-specific differentiation. CpG methylation in promoter regions, gene bodies, or enhancers can either silence or promote transcription depending on the genomic context. The landmark study by [PERSON] et al. [8] provided compelling evidence that differential DNA methylation profiles among DPSCs, PDLSCs, and DEFPCs are associated with their osteogenic potential. While the global methylation landscapes of the three cell types were largely similar, key differences emerged in genes related to bone formation, extracellular matrix organization, and signaling regulation. Notably, PDLSCs showed hypomethyllation of osteogenic transcription factors, correlating with their enhanced in vitro and in vivo bone-forming ability.  
Epigenomic profiling technologies, such as the array-based technologies, have enabled high-resolution interrogation of methylation states across the genome [9]. These platforms have facilitated the identification of differentially methylated CpG sites and their association with gene regulatory elements. When integrated with gene ontology and pathway analyses, methylation data can reveal functionally relevant epigenetic signatures that govern stem cell identity and behavior [10; 11]. In this study, publicly available methylation data (GSE12933) [8] from DPSCs, PDLSCs, and DEFPCs were reanalyzed. The objective is to identify both shared and lineage-specific epigenetic profiles using an updated bioinformatic pipeline. Special emphasis is placed on functionally annotated CpG regions, including those located in promoters, enhancers, and noncoding RNA loci. Through integrative analysis of methylation variability, clustering, and gene set enrichment, the aim is to elucidate the molecular logic that underpins odontogenic differentiation and provides insight into the epigenetic basis of dental stem cell diversity.