GSE158167
The chromatin remodeler Brg1 cooperates with tissue-specific transcription-factors to regulate Sox2 activation via multiple enhancers to establish proneurosensory identity within otic ectoderm
Specification of Sox2+ proneurosensory progenitors within otic ectoderm is a prerequisite for the production of sensory cells and neurons for hearing. However, the underlying molecular mechanisms driving this lineage specification remain unknown. Here, we show that Brg1-based SWI/SNF chromatin-remodeling complex interacts with the neurosensory-specific transcriptional regulators Eya1/Six1 to induce Sox2 expression and proneurosensory-lineage specification. Ablation of the ATPase-subunit Brg1 or both Eya1/Six1 results in loss of Sox2 expression and lack of neurosensory identity. Brg1 and Six1 co-occupy three distal 3' Sox2 enhancers and Brg1-recruitment to these regions is disrupted in Eya1- or Six1-null otocyst. Eya1 as a coactivator of Six1 synergistically regulates the activity of these enhancers, which drives expression in otic neurosensory cells in response to binding to Six1. Thus, through interaction with Six1/Eya1, the Brg1-based SWI/SNF complex specifies otic proneurosensory lineage. Furthermore, genome-wide and transcriptome analyses reveal that Brg1 also suppresses expression of non-otic genes. Overall design: We sequenced RNA isolated from otic cells FACS-purified from control and Brg1-cKO otocysts.