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

Author

Listed:
  • Xuyao Chang

    (Cincinnati Children’s Hospital Medical Center
    Cincinnati Children’s Hospital Medical Center)

  • Wenqi Li

    (University of Texas Southwestern Medical Center and Children’s Medical Center Dallas
    University of Texas Southwestern Medical Center)

  • Satoshi Matsui

    (Cincinnati Children’s Hospital Medical Center
    Osaka University)

  • 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
    University of Cincinnati College of Medicine)

  • Amelle Shillington

    (University of Cincinnati College of Medicine
    Cincinnati Children’s Hospital Medical Center)

  • Constantinos Chronis

    (University of Illinois College of Medicine)

  • Jason Tchieu

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine)

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.

Suggested Citation

  • 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, 2025. "ZMYND11 functions in bimodal regulation of latent genes and brain-like splicing to safeguard corticogenesis," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64063-0
    DOI: 10.1038/s41467-025-64063-0
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