ZMYND11 Functions in Bimodal Regulation of Latent Genes and Brain-like Splicing to Safeguard Corticogenesis

• DOI: 10.1101/2024.10.15.618524
• Publication Date: 2024-10-16T09:10:11Z
• Authors: Xuyao Chang; Wenqi Li; Satoshi Matsui; Cindy Huynh; Gustav Y. Cederquist; Lorenz Studer; Makiko Iwafuchi; Amelle Shillington; Constantinos Chronis; Jason Tchieu
• Keywords: Corticogenesis; Safeguard

Abstract Despite the litany of pathogenic variants linked to neurodevelopmental disorders (NDD) including autism (ASD) and intellectual disability 1,2 , our understanding underlying mechanisms caused by risk genes remain unclear. Here, we leveraged a human pluripotent stem cell model uncover consequences mutations in ZMYND11 newly implicated gene 3,4 . ZMYND11, known for its tumor suppressor function, encodes histone-reader that recognizes sites transcriptional elongation acts as co-repressor 5,6 Our findings reveal ZMYND11-deficient cortical neural cells showed upregulation latent developmental pathways, impairing progenitor neuron production. In addition role on histones, controls brain-specific isoform switch involving splicing regulator RBFOX2. Extending other chromatin-related ASD factors revealed similar pathway activation dysregulation, partially rescuable through ZMYND11’s regulatory functions.