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<p>Genetic and epigenetic variations contribute to the progression of glioma, but the mechanisms underlying these effects, particularly for enhancer-associated genetic variations in non-coding regions, still remain unclear. Here we performed high-throughput CRISPR interference screening to identify pro-tumour enhancers in glioma cells. By integrating genome-wide H3K27ac HiChIP data, we identified the target genes of these pro-tumour enhancers and revealed the essential role of enhancer connectomes in promoting glioma progression. Through systematic analysis of enhancers carrying glioma risk-associated single-nucleotide polymorphisms (SNPs), we found that these SNPs can promote glioma progression through the enhancer connectome. Using CRISPR–Cas9-mediated enhancer interference and SNP editing, we demonstrated that glioma-specific enhancer carrying the risk SNP <a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs2297440">rs2297440</a> regulates <i>SOX18</i> expression by specifically recruiting transcription factor MEIS1 binding, thereby contributing to glioma progression. Our study sheds light on the molecular mechanisms underlying glioma susceptibility and provides potential therapeutic targets to treat glioma.</p>

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Systematic decoding of functional enhancer connectomes and risk variants in human glioma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月19日

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  • Jinfang Bi,
  • Weipeng Mo,
  • Man Liu,
  • Yingjie Song,
  • Qian Xiao,
  • Sibo Fan,
  • Wenbin Wang,
  • Tengfei Shi,
  • Yaoqiang Zheng,
  • Jie Lian,
  • Rong Liu,
  • Bohan Chen,
  • Xiaofeng Huang,
  • Peng Li,
  • Zhongfang Zhao,
  • Jiandang Shi,
  • Lei Zhang,
  • Guangsong Su,
  • Nu Zhang,
  • Wange Lu

摘要

Genetic and epigenetic variations contribute to the progression of glioma, but the mechanisms underlying these effects, particularly for enhancer-associated genetic variations in non-coding regions, still remain unclear. Here we performed high-throughput CRISPR interference screening to identify pro-tumour enhancers in glioma cells. By integrating genome-wide H3K27ac HiChIP data, we identified the target genes of these pro-tumour enhancers and revealed the essential role of enhancer connectomes in promoting glioma progression. Through systematic analysis of enhancers carrying glioma risk-associated single-nucleotide polymorphisms (SNPs), we found that these SNPs can promote glioma progression through the enhancer connectome. Using CRISPR–Cas9-mediated enhancer interference and SNP editing, we demonstrated that glioma-specific enhancer carrying the risk SNP rs2297440 regulates SOX18 expression by specifically recruiting transcription factor MEIS1 binding, thereby contributing to glioma progression. Our study sheds light on the molecular mechanisms underlying glioma susceptibility and provides potential therapeutic targets to treat glioma.