Neural crest induction requires SALL4-mediated BAF recruitment to lineage specific enhancers

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 highly expressed in cranial neural crest cells (CNCCs) and associated with syndromes featuring craniofacial anomalies, plays a critical role in this early regulatory process. Using SALL4-haploinsufficient human iPSC models that recapitulate clinical haploinsufficiency, we show that SALL4 directly interacts with the BAF chromatin remodeling complex at the neuroectodermal stage, specifically when neural crest lineage specific gene expression is induced from the neural plate border. The SALL4-BAF interaction at this stage is essential for the recruitment of BAF to CNCC-induction enhancers. Without functional SALL4, BAF is not loaded at chromatin, leaving CNCC enhancers inaccessible. Consequently, the cells cannot undergo proper CNCC induction and specification due to persistent enhancer repression, despite normal neuroectodermal and neural plate progression. Moreover, by performing SALL4 isoform-specific depletion, we demonstrate that the SALL4A is the isoform essential for CNCC induction and specification, and that SALL4B cannot compensate for SALL4A loss in this developmental process.

In summary, our findings reveal SALL4 as essential regulator of BAF-dependent enhancer activation during early stages of neural crest development, providing molecular insights into SALL4-associated craniofacial anomalies.