Epigenomic regulation of neural crest differentiation in human-induced pluripotent stem cells

Summary Neural crest cells (NCCs) drive vertebrate development through lineage specific differentiation into diverse tissues. Cranial (cNCCs) and trunk NCCs (tNCCs) exhibit distinct developmental trajectories that require coordinated epigenomic regulation. Aberrant NCC differentiation is associated with diseases including tumors. Epigenetic mechanisms such as histone modifications and DNA methylation are crucial for regulating NCC differentiation. Here, we used a human induced pluripotent stem cell model to compare differentiation of cNCCs and tNCCs and define lineage specific mechanisms. Integrated transcriptome and DNA methylome analyses revealed that DNA demethylation upstream of MEF2C in cNCCs and the THRA locus (a shared promoter region for THRA1 and THRA2 isoforms) in tNCCs was associated with increased expression of MEF2C and THRA2. MEF2C and THRA2 were associated with NCC markers. These findings define epigenomic features underlying lineage divergence and provide insight into NCC-related diseases such as leiomyosarcoma and neuroblastoma.