GSE202956
The transcriptional coactivator Eya1 exerts transcriptional repressive activity by interacting with REST corepressors and DNA recognition sequences to maintain nephron progenitor identity [RNA-seq]
Eya1 is critical for specifying and maintaining nephron progenitor cells (NPCs). It belongs to a protein family known as phosphatase-transcriptional activator but without intrinsic DNA-binding activity. However, the Eya1-centered network and the spectrum of its interaction partners are underexplored. Here, we combined transcriptomic, genomic and proteomic approaches to characterize gene regulation by Eya1 in the NPCs. We identified Eya1 target genes, genomic binding sites, and partner proteins. Eya1 binds preferentially to promoter sequences and interacts with general transcription factors (TFs), RNA polymerases, different types of TFs, and DNA replication/repair proteins. Intriguingly, we identified REST-binding motifs in 76% of Eya1-binding sites without H3K27ac-deposition, which were present in many Eya1 target genes upregulated in Eya1-deficient NPCs. Eya1 copurified REST-interacting proteins, including chromatin-remodeling factors with ATPase or helicase activity, histone deacetylase/lysine demethylase, and corepressors. Coimmunoprecipitation validated complex formation between Eya1, Hdac1 and Cdyl in kidneys. Thus, these results suggest that through interactions with chromatin-remodeling factors, Eya1 may modify chromatin structure to facilitate the assembly of regulatory complexes that regulate transcription positively or negatively. These findings provide a mechanistic basis for how Eya1 functions as a multifunction protein by cooperating with protein partners in various fundamental biological processes to maintain the cellular state of NPCs. Overall design: Mouse kidneys from Wt and Eya1 conditional knockout embryos