ZMYND11 functions in bimodal regulation of latent genes and brain-like splicing to safeguard corticogenesis
Year: 2025
Type: article
Abstract: Despite the numerous pathogenic variants linked to neurodevelopmental disorders (NDDs) including autism (ASD) and intellectual disability, our understanding of the underlying mechanisms caused by risk genes remain unclear. Here, we show that mutations in ZMYND11, a newly implicated risk gene, impair human cortical progenitor and neuron production. ZMYND11, known for its tumor suppressor function, encodes a histone-reader that recognizes sites of transcriptional elongation and acts as a co-repressor. ZMYND11-deficient cortical neural stem cells upregulate inappropriate developmental pathways, leading to disrupted neurogenesis. In addition to its role on chromatin, ZMYND11 regulates a brain-specific RNA isoform switch involving the splicing regulator RBFOX2. Similar defects are observed in other chromatin-related ASD risk genes, some of which are partially rescued by enhancing ZMYND11 function. These findings uncover convergent pathways linking chromatin regulation and splicing to human brain development and advance our understanding of how genetic risk contributes to NDD.
Source: Nature Communications
Authors: Xuyao Chang, Wenqi Li, Satoshi Matsui, Cindy Huynh, Craig Erickson, Feng Guo, Gustav Y. Cederquist, Lorenz Studer, Makiko Iwafuchi, Amelle Shillington, Constantinos Chronis, Jason Tchieu
Institutions: Cincinnati Children's Hospital Medical Center, Children's Medical Center, The University of Texas Southwestern Medical Center, The University of Osaka, Indiana University Bloomington, Indiana University, Memorial Sloan Kettering Cancer Center, University of Cincinnati, University of Illinois Chicago
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: U.S. Department of Defense, U.S. Department of Health and Human Services, Memorial Sloan-Kettering Cancer Center, Cincinnati Children's Hospital Medical Center, Starr Foundation, Cincinnati Children’s Research Foundation, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences
Awards: G2110784777, G289723095, G4119534169, IS THERE A POINT OF CONVERGENCE BETWEEN CONGENITAL HEART DISEASE AND AUTISM?, G5850682332, G6561279298, Dynamic regulation of lineage-specific Polycomb repressive landscapes by pioneer and PRDM transcription factors, G8444108020, G9000028227, Cancer Center Support Grant
OpenAlex ID: W4414984207