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<p>The <i>FOXG1</i> transcription factor is a crucial regulator of embryonic brain development. Pathogenic <i>FOXG1</i> variants cause <i>FOXG1</i> syndrome. Although structural variants in the non-coding region downstream of <i>FOXG1</i> have been reported in 38 individuals with similar characteristics, the regulatory pathomechanisms remain unknown. Here, we identify two non-coding structural variants in individuals with <i>FOXG1</i> syndrome-like features, allowing us to delineate a ~ 124 kb commonly affected regulatory region. Using epigenomic profiling and in vivo enhancer assays, we characterize and validate regulatory elements within the commonly affected regulatory region and wider <i>FOXG1</i> TAD. We see strong activation of previously validated forebrain enhancers, and identify an enhancer cluster and progenitor-specific enhancer region that are strongly activated during forebrain-directed neural progenitor cell differentiation, a process in which <i>FOXG1</i> is an important regulator. Perturbation of these elements results in varying degrees of reduced <i>FOXG1</i> transcription in forebrain neural progenitor cells and in population shifts within these cells, while removal of the TAD boundary leads to aberrant expression of the neighbouring <i>PRKD1</i> gene. Our findings characterize enhancer and architectural elements essential for proper <i>FOXG1</i> transcription during neurodevelopment, therefore improving variant interpretation in this region.</p>

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Non-coding structural variants disrupt FOXG1 transcriptional regulation in early neurodevelopment

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月3日

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  • Lisa Hamerlinck,
  • Eva D’haene,
  • Michael B. Vaughan,
  • Nore Van Loon,
  • María del Rocío Pérez Baca,
  • Sebastian Leimbacher,
  • Michael Kosicki,
  • Lara Colombo,
  • Lukas Genbrugge,
  • Lies Vantomme,
  • Esperanza Daal,
  • Luiza Lorena Pires Ramos,
  • Daniela Mircheva Avdjieva-Tzavella,
  • Himanshu Goel,
  • Koen Devriendt,
  • Albena Jordanova,
  • Annelies Dheedene,
  • Axel Visel,
  • Björn Menten,
  • Bert Callewaert,
  • Sarah Vergult

摘要

The FOXG1 transcription factor is a crucial regulator of embryonic brain development. Pathogenic FOXG1 variants cause FOXG1 syndrome. Although structural variants in the non-coding region downstream of FOXG1 have been reported in 38 individuals with similar characteristics, the regulatory pathomechanisms remain unknown. Here, we identify two non-coding structural variants in individuals with FOXG1 syndrome-like features, allowing us to delineate a ~ 124 kb commonly affected regulatory region. Using epigenomic profiling and in vivo enhancer assays, we characterize and validate regulatory elements within the commonly affected regulatory region and wider FOXG1 TAD. We see strong activation of previously validated forebrain enhancers, and identify an enhancer cluster and progenitor-specific enhancer region that are strongly activated during forebrain-directed neural progenitor cell differentiation, a process in which FOXG1 is an important regulator. Perturbation of these elements results in varying degrees of reduced FOXG1 transcription in forebrain neural progenitor cells and in population shifts within these cells, while removal of the TAD boundary leads to aberrant expression of the neighbouring PRKD1 gene. Our findings characterize enhancer and architectural elements essential for proper FOXG1 transcription during neurodevelopment, therefore improving variant interpretation in this region.