Demurtas, M.; Barnada, S. M.; Van Domeslaar, E.; Mitchell, Z. H.; Deelen, L. L.; Trizzino, M.

Neural crest induction begins early during neural plate formation, requiring precise transcriptional control to activate lineage-specific enhancers. Here, we demonstrate that SALL4, a transcription factor strongly expressed in cranial neural crest cells (CNCCs) and associated with syndromes featuring craniofacial anomalies, plays a critical role in this early regulatory process. Using a SALL4-haploinsufficient human iPSC model that recapitulates clinical haploinsufficiency, we show that the SALL4A isoform directly interacts with the BAF complex subunit DPF2 through its zinc-finger-3 domain. This interaction enables SALL4-mediated recruitment of BAF to CNCC-specific enhancers during early neural plate stages. Without functional SALL4, BAF fails to load at chromatin, leaving CNCC enhancers inaccessible despite normal neuroectodermal progression. Consequently, cells cannot undergo proper CNCC induction and specification due to persistent enhancer repression. Our findings reveal SALL4 as an essential regulator of BAF-dependent enhancer activation during early neural crest development, providing molecular insights into SALL4-associated craniofacial anomalies.