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<p>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 <i>ZMYND11</i>, 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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月9日

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  • 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

摘要

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.