Brg1 controls neurosensory cell fate commitment and differentiation in the mammalian inner ear

Abstract

Otic ectoderm gives rise to almost all cell types of the inner ear; however, the mechanisms that link transcription factors, chromatin, lineage commitment and differentiation capacity are largely unknown. Here we show that Brg1 chromatin-remodeling factor is required for specifying neurosensory lineage in the otocyst and for inducing hair and supporting cell fates in the cochlear sensory epithelium. Brg1 interacts with the critical neurosensory-specific transcription factors Eya1/Six1, both of which simultaneously interact with BAF60a or BAF60c. Chromatin immunoprecipitation-sequencing (ChIP-seq) and ChIP assays demonstrate Brg1 association with discrete regulatory elements at the Eya1 and Six1 loci. Brg1-deficiency leads to markedly decreased Brg1 binding at these elements and loss of Eya1 and Six1 expression. Furthermore, ChIP-seq reveals Brg1-bound promoter-proximal and distal regions near genes essential for inner ear morphogenesis and cochlear sensory epithelium development. These findings uncover essential functions for chromatin-remodeling in the activation of neurosensory fates during inner ear development.