Modeling neurodevelopmental disorder-associated human AGO1 mutations in C. elegans Argonaute alg-1. [ribosome profiling]

ABSTRACT: MicroRNAs (miRNA) associate with Argonaute proteins and negatively regulate gene expression by base pairing with complementary sequences in the 3’ UTRs of target genes. De novo coding variants in the human Argonaute gene AGO1 were reported to cause neurodevelopmental disorder (NDD) with intellectual disability (ID). Most of the altered amino acids are conserved between the miRNA associated Argonautes in H. sapiens and C. elegans, suggesting that the human AGO1 mutations could disrupt evolutionarily conserved functions in miRNA biogenesis or target repression. We genetically modeled four human AGO1 mutations in C. elegans by introducing identical mutations into the C. elegans AGO1 homolog, ALG-1. These alg-1 NDD mutations caused phenotypes in C. elegans indicative of disrupted miRNA processing, miRISC formation, and/or target repression. We show that the alg-1 NDD mutations are antimorphic as they cause developmental and molecular phenotypes stronger than those exhibited by the alg-1 null mutants, likely by sequestrating functional miRNA silencing complex (miRISC) components into non-functional complexes that fail to confer robust gene repression. The alg-1 NDD mutations cause allele-specific disruptions in mature miRNA profiles, both in overall abundances and ALG-1 NDD association, accompanied by perturbation of downstream gene expression, including altered translational efficiency and/or mRNA abundance. The perturbed genes include those with human orthologs whose dysfunction is associated with NDD. These cross-clade genetic studies illuminate fundamental Argonaute functions and provide insights into the conservation of miRNA-mediated post-transcriptional regulatory mechanisms.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE252063 | GEO | 2023/12/30

REPOSITORIES: GEO