Inhibition of the chromatin remodeling factor NURF rescued sterility by a clinic variant of NuRD

Abstract

The nucleosome remodeling and deacetylase (NuRD) complex is essential for gene expression and cell fate determination, and missense mutations of NuRD caused neurodevelopmental diseases. However, the molecular pathogenesis of clinic NuRD variants is unknown. Here, we introduced a clinic CHD3 (L915F) variant into Caenorhabditis elegans homologue LET-418, impairing germline and vulva development and ultimately causing animal sterility. Our ATAC-seq and RNA-seq analyses revealed that this variant generated an abnormal open chromatin structure and disrupted the expression of developmental genes. Through genetic suppressor screens, we uncovered that intragenic mutations, likely renovating NuRD activity, restored animal viability. We also found that intergenic mutations in nucleosome remodeling factor NURF that counteracts NuRD rescued abnormal chromatin structure, gene expression, and animal sterility. We propose that two antagonistic chromatin-remodeling factors coordinate to establish the proper chromatin status and transcriptome and that inhibiting NURF may provide insights for treatment of NuRD mutation-related diseases.