ZMYND11 functions in bimodal regulation of latent genes and brain-like splicing to safeguard corticogenesis
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.
Authors
- Craig A. Erickson (ORCID: https://orcid.org/0000-0003-4512-398X)
- Satoshi� Matsui (ORCID: https://orcid.org/0000-0002-6315-4109)
- G. Cederquist (ORCID: https://orcid.org/0000-0003-4749-6093)
- Feng Guo (ORCID: https://orcid.org/0000-0001-9103-3235)
- Xuyao Chang (ORCID: https://orcid.org/0000-0002-7646-9521)
- Makiko Iwafuchi (ORCID: https://orcid.org/0000-0003-1291-6246)
- Amelle Shillington (ORCID: https://orcid.org/0000-0002-7447-8117)
- Jason Tchieu (ORCID: https://orcid.org/0000-0002-9793-9836)
- Cathy Huynh (ORCID: https://orcid.org/0000-0001-8487-3076)
- Constantinos Chronis (ORCID: https://orcid.org/0000-0002-7783-8202)
- Lorenz Studer (ORCID: https://orcid.org/0000-0003-0741-7987)
- Wenqi Li (ORCID: https://orcid.org/0000-0003-0751-2968)
Institutions
- Cincinnati Children's Hospital Medical Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of Illinois Urbana-Champaign (US)
- Illinois College (US)
- University of Illinois Chicago (US)
- Indiana University Bloomington (US)
- The University of Texas Southwestern Medical Center (US)
- University of Cincinnati Medical Center (US)
- The University of Osaka (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-09
- DOI
- https://doi.org/10.1038/s41467-025-64063-0
- Citations
- 2
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- U.S. Department of Defense
- Memorial Sloan-Kettering Cancer Center
- Cincinnati Children's Hospital Medical Center
- National Institutes of Health