近日，南开大学吕万革及其小组研制了人类胶质瘤中功能增强子连接体和风险变异的系统解码。这一研究成果于2025年8月19日发表在国际顶尖学术期刊《自然—细胞生物学》上。

在这里，课题组人员进行了高通量CRISPR干扰筛选，以鉴定胶质瘤细胞中的促肿瘤增强子。通过整合全基因组H3K27ac HiChIP数据，课题组人员确定了这些促肿瘤增强子的靶基因，并揭示了增强子连接体在促进胶质瘤进展中的重要作用。通过系统分析携带胶质瘤风险相关单核苷酸多态性（SNPs）的增强子，小组发现这些SNPs可以通过增强子连接组促进胶质瘤的进展。通过CRISPR–Cas9介导的增强子干扰和SNP编辑，该课题组人员证明了携带风险SNP rs2297440的胶质瘤特异性增强子通过特异性募集转录因子MEIS1结合来调节SOX18的表达，从而促进胶质瘤的进展。他们的研究揭示了神经胶质瘤易感性的分子机制，为治疗神经胶质瘤提供了潜在的治疗靶点。

据了解，遗传和表观遗传变异有助于胶质瘤的进展，但这些影响的机制，特别是在非编码区增强子相关的遗传变异，仍然不清楚。

附：英文原文

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

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

Issue&Volume: 2025-08-19

Abstract: 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.

DOI: 10.1038/s41556-025-01737-3

Source: https://www.nature.com/articles/s41556-025-01737-3