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<p>Dravet syndrome (DS) is a severe neurodevelopmental disorder associated with physical and cognitive impairments, often attributed to mutations in the <i>SCN1A</i> gene. However, gene regulatory features that modulate <i>SCN1A</i> expression found in vivo and in vitro models remain elusive. This study elucidates cell type-specific cis-regulatory elements (CRE) regulating <i>SCN1A</i> expression in cortical fast-spiking GABAergic inhibitory interneurons, the predominantly affected cell type in DS. We establish a differentiation protocol from human induced pluripotent stem cells (iPSCs) for both healthy control and DS patient-derived lines, followed by single-cell 5′ RNA-seq at different stages of interneuron maturation. Through this analysis, we identify interneuron-enriched transcriptional start sites (TSSs) in cell type-restricted promoters regulated by a distinct set of transcription factors. Furthermore, we investigate <i>SCN1A</i> anti-sense (AS) transcripts and emphasize the importance of accurate 5′ gene annotation in the context of developing targeted gene therapeutics. This work highlights the complexities and dynamics of studying DS at the molecular level and the need for comprehensive gene regulation analysis in vitro and ex vivo to enable precision medicine therapeutic approaches for DS.</p>

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Defining the Cis-Regulatory Elements of SCN1A in GABAergic Interneurons

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月23日

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  • Joachim Luginbühl,
  • Anika V. Prabhu,
  • Chi Wai Yip,
  • Yoshinari Ando,
  • Julio Leon,
  • Kayoko Yasuzawa,
  • Chung Chau Hon,
  • Jonathan Moody,
  • Filip Roudnicky,
  • Thomas Kremer,
  • Jay W. Shin

摘要

Dravet syndrome (DS) is a severe neurodevelopmental disorder associated with physical and cognitive impairments, often attributed to mutations in the SCN1A gene. However, gene regulatory features that modulate SCN1A expression found in vivo and in vitro models remain elusive. This study elucidates cell type-specific cis-regulatory elements (CRE) regulating SCN1A expression in cortical fast-spiking GABAergic inhibitory interneurons, the predominantly affected cell type in DS. We establish a differentiation protocol from human induced pluripotent stem cells (iPSCs) for both healthy control and DS patient-derived lines, followed by single-cell 5′ RNA-seq at different stages of interneuron maturation. Through this analysis, we identify interneuron-enriched transcriptional start sites (TSSs) in cell type-restricted promoters regulated by a distinct set of transcription factors. Furthermore, we investigate SCN1A anti-sense (AS) transcripts and emphasize the importance of accurate 5′ gene annotation in the context of developing targeted gene therapeutics. This work highlights the complexities and dynamics of studying DS at the molecular level and the need for comprehensive gene regulation analysis in vitro and ex vivo to enable precision medicine therapeutic approaches for DS.