Cohesin composition and dosage independently affect early development in zebrafish

Abstract

Cohesin, a chromatin-associated protein complex with four core subunits (Smc1a, Smc3, Rad21 and either Stag1 or 2), has a central role in cell proliferation and gene expression in metazoans. Human developmental disorders termed “cohesinopathies” are characterised by germline mutations in cohesin or its regulators that do not entirely eliminate cohesin function. However, it is not clear if mutations in individual cohesin subunits have independent developmental consequences. Here we show that zebrafishrad21orstag2mutants independently influence embryonic tailbud development. Both mutants have altered mesoderm induction, but only homozygous or heterozygousrad21mutation affects cell cycle gene expression.stag2mutants have narrower notochords and reduced Wnt signaling in neuromesodermal progenitors as revealed by single cell RNA-sequencing.Stimulation of Wnt signaling rescues transcription and morphology instag2, but notrad21mutants. Our results suggest that mutations altering the quantity versus composition of cohesin have independent developmental consequences, with implications for the understanding and management of cohesinopathies.TeaserViable zebrafish mutants show that cohesin complex quantity versus composition lead to different transcriptional and developmental outcomes in the early embryo.