Systematic decoding of functional enhancer connectomes and risk variants in human glioma
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.
Authors
- Nu Zhang (ORCID: https://orcid.org/0000-0002-2817-7065)
- Zhongfang Zhao
- Qian Xiao (ORCID: https://orcid.org/0000-0002-3665-9590)
- Weipeng Mo (ORCID: https://orcid.org/0000-0002-2955-8310)
- Jinfang Bi
- Jiandang Shi (ORCID: https://orcid.org/0000-0002-3530-1167)
- Peng Li (ORCID: https://orcid.org/0000-0002-7689-2645)
- Wange Lu (ORCID: https://orcid.org/0000-0001-5848-3189)
- Yingjie Song (ORCID: https://orcid.org/0009-0004-4712-602X)
- Rong Liu (ORCID: https://orcid.org/0000-0003-2561-348X)
- Xiaofeng Huang (ORCID: https://orcid.org/0009-0000-3627-3711)
- Bohan Chen (ORCID: https://orcid.org/0000-0002-9781-2982)
- Yaoqiang Zheng
- Man Liu (ORCID: https://orcid.org/0000-0001-5265-8224)
- Lei Zhang (ORCID: https://orcid.org/0000-0003-4381-3696)
- Sibo Fan
- Jie Lian (ORCID: https://orcid.org/0000-0002-7237-7347)
- Guangsong Su
- Tengfei Shi (ORCID: https://orcid.org/0000-0001-6885-1619)
- Wenbin Wang
Institutions
- Sun Yat-sen University (CN)
- Nankai University (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Guangdong 999 Brain Hospital (CN)
Publication Details
- Journal
- Nature Cell Biology
- Published
- 2025-08-19
- DOI
- https://doi.org/10.1038/s41556-025-01737-3
- Citations
- 2
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation