The BAF chromatin remodeling subunit ARID1B coordinates cell-cycle exit and motor neuron differentiation

Neuronal differentiation requires precise regulation of transcriptional and epigenetic networks by BAF (BRG1/BRM-associated factor) chromatin remodeling complexes. Mutations in Arid1b, encoding a core BAF subunit, are associated with motor dysfunction, yet the role of ARID1B in motor neuron specification remains unclear. Using Arid1b knockout mouse embryonic stem cells, we show that ARID1B is not required for neural progenitor specification but is essential for the transition to postmitotic motor neurons. Arid1b knockout impairs cell-cycle exit and neurite outgrowth, reducing neuronal gene expression while maintaining early developmental and cell-cycle gene expression. Mechanistically, ARID1B-containing BAF complexes are recruited to neuronal gene promoters enriched for active chromatin signatures and the neuron-associated transcription factor NRF1 binding. The histone acetyltransferase p300 preferentially occupies ARID1B/BRG1 co-bound regions enriched with histone H3 lysine 27 acetylation (H3K27ac), and loss of ARID1B alters H3K27ac enrichment associated with neuronal gene expression. Together, these findings establish ARID1B as a critical regulator coordinating the developmental switch from cell-cycle progression to motor neuron differentiation.