EHMT2 Controls Neural Crest-Derived Craniofacial Development but is Dispensable in Limb Development.

Post-translational modifications of histones, such as methylation of histone H3 at lysine 9 (H3K9), play critical roles in regulating chromatin structure and gene expression. EHMT2 (also called G9A), a histone methyltransferase, mediates H3K9 mono- and dimethylation and has been implicated in both transcriptional repression and context-specific gene activation. Although global knockout of the mouse gene results in early embryonic lethality, tissue-specific knockouts have uncovered diverse roles in organ development. However, how EHMT2 contributes to skeletal development in a lineage-specific manner remains to be fully elucidated. Here, we investigated the role of EHMT2 in skeletal development by conditionally inactivating in neural crest-derived and mesoderm-derived progenitors using and mouse lines, respectively. Loss of function in neural crest cells led to postnatal growth failure and craniofacial defects, including delayed intramembranous ossification and malformations of the jaw and cranial base. Transcriptomic analysis of neural crest cells revealed disrupted chromatin regulatory networks, reduced expression of proliferation-associated genes, and upregulation of inflammatory pathways. In contrast, inactivation of in -expressing mesodermal progenitors had minimal impact on limb and cranial bone development, with no significant alterations in bone mass or osteoblast function. Together, these results reveal a lineage-specific requirement for EHMT2 in neural crest-derived skeletal tissues, suggesting that distinct progenitor populations exhibit differential dependency for bone development.