ZMYND11 functions in bimodal regulation of latent genes and brain-like splicing to safeguard corticogenesis

Xuyao Chang, Wenqi Li, Satoshi Matsui, Cindy Huynh, Craig Erickson, Feng Guo, Gustav Y. Cederquist, Lorenz Studer, Makiko Iwafuchi, Amelle Shillington, Constantinos Chronis and Jason Tchieu ()
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Xuyao Chang: Cincinnati Children’s Hospital Medical Center
Wenqi Li: University of Texas Southwestern Medical Center and Children’s Medical Center Dallas
Satoshi Matsui: Cincinnati Children’s Hospital Medical Center
Cindy Huynh: Cincinnati Children’s Hospital Medical Center
Craig Erickson: Cincinnati Children’s Hospital Medical Center
Feng Guo: Indiana University Bloomington
Gustav Y. Cederquist: Memorial Sloan Kettering Cancer Center
Lorenz Studer: Memorial Sloan Kettering Cancer Center
Makiko Iwafuchi: Cincinnati Children’s Hospital Medical Center
Amelle Shillington: University of Cincinnati College of Medicine
Constantinos Chronis: University of Illinois College of Medicine
Jason Tchieu: Cincinnati Children’s Hospital Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64063-0

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