CREST functions as a molecular bridge between neuron-specific enhancers and epigenetic regulators in mature motor neurons

Motor neuron development requires precise transcriptional regulation mediated in part by BAF (BRG1/BRM-associated factor) chromatin remodeling complexes. The neuron-specific BAF subunit CREST is critical for neuronal function and is mutated in some cases of amyotrophic lateral sclerosis (ALS), yet its underlying genomic mechanisms remain unclear. Using mouse embryonic stem cell differentiation, we show that CREST is essential for motor neuron maturation by activating mature neuronal genes and repressing progenitor genes. Mechanistically, CREST interacts with the neuronal transcription factors ONECUT1 and NGN2, and the BRM ATPase to target pre-existing accessible enhancers of neuronal genes. CREST deletion selectively prevents CBP histone acetyltransferase recruitment, reducing histone H3K27 acetylation at these enhancers and downregulating target gene expression, without disrupting BRM binding, enhancer accessibility, or long-range chromatin architecture. Overall, our findings identify CREST as a crucial epigenetic mediator bridging lineage-specific transcription factors, BAF complexes, and CBP to activate enhancers and promote proper motor neuron development.