Enhancer plasticity in endometrial tumorigenesis demarcates non-coding driver mutations and 3D genome alterations to stimulate oncogene expression [Hi-C_ECa_patients]

The incidence and mortality of Endometrial Cancer (EC) is on the rise. 85% of ECs depend on Estrogen Receptor alpha (ERα) for proliferation, but little is known about its transcriptional regulation in these tumors. We generated epigenomics and Hi-C data streams in healthy and tumor endometrial tissues, identifying robust ERa reprogramming and profound alterations in 3D genome organization that lead to a gain of tumor-specific enhancer activity during EC development. Integration with WGS data from metastatic samples revealed a striking enrichment of non-coding somatic mutations at tumor-enriched ERa sites. Through machine learning-based predictions and interaction proteomics analyses, we identified an enhancer mutation which alters 3D genome organization, impairing recruitment of the transcriptional repressor EHMT2/G9a/KMT1C, thereby alleviating transcriptional repression of ESR1 in EC. In summary, we identified a complex genomic-epigenomic interplay in EC development and progression, altering 3D genome organization to enhance expression of the critical driver ERα. For Hi-C libraries preparation we used 3x10 50um-thick slices of flash frozen tissue derived from 3 healthy and 3 tumor endometrial tissues of post-menopausal patients. *************************************************************** Raw data are available at EGA under restricted access: EGAS00001007240 ***************************************************************

子宫内膜癌（Endometrial Cancer, EC）的发病率与死亡率呈逐年上升态势。其中85%的子宫内膜癌增殖依赖于雌激素受体α（Estrogen Receptor alpha, ERα），但目前针对此类肿瘤中ERα的转录调控机制仍知之甚少。我们于健康及肿瘤子宫内膜组织中构建了表观基因组学与Hi-C数据流，鉴定出显著的ERα重编程事件，以及深刻改变的3D基因组组织结构——此类改变在子宫内膜癌发生过程中赋予了肿瘤特异性增强子活性。结合转移性样本的全基因组测序（Whole Genome Sequencing, WGS）数据进行整合分析后，我们发现肿瘤富集的ERα结合位点存在显著的非编码体细胞突变富集现象。借助基于机器学习的预测与相互作用蛋白质组学分析，我们鉴定出一处增强子突变：该突变可改变3D基因组组织结构，削弱转录抑制因子EHMT2/G9a/KMT1C的招募，进而缓解子宫内膜癌中ESR1基因的转录抑制。综上，我们揭示了子宫内膜癌发生发展过程中复杂的基因组-表观基因组互作机制，即通过重塑3D基因组结构以增强关键驱动因子ERα的表达。对于Hi-C文库的制备，我们使用了来自3名绝经后健康女性与3名绝经后子宫内膜癌患者的速冻组织样本，每份样本制备3×10片厚度为50μm的切片。
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原始数据可通过受限访问的欧洲基因组表型档案（European Genome-phenome Archive, EGA）获取：EGAS00001007240
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