生物信息学新方法鉴定乳腺癌增强子并分析其潜在功能

Identification of Breast Cancer Enhancers and Analyzing Their Potential Functions by Using Novel Bioinformatics Method

乳腺癌是威胁女性生命的一大危险因素。激活与癌症发生发展和细胞多能性相关的增强子或抑制维持细胞命运的增强子均可导致“细胞身份危机”,使细胞趋向去分化状态进而癌变。本研究运用新的生物信息学方法,通过深入分析癌症基因组图谱(the cancer genome atlas,TCGA)数据库的乳腺癌全转录组测序数据,鉴定乳腺癌相关增强子并量化增强子RNA(enhancer RNA,eRNA),预测其对靶基因的调控活性,同时探讨活性异常增强子在乳腺癌发生发展过程中的潜在作用。在112对乳腺癌患者的肿瘤与癌旁组织中鉴定得到47921个eRNAs,其中4830个eRNAs在肿瘤和癌旁组织间存在显著的表达差异,有666个差异表达eRNA的增强子位点与已知的乳腺癌相关基因组变异位点重叠。通过计算转录因子与增强子位点结合的亲和力发现部分增强子突变位点可能导致转录因子亲和力改变,影响增强子活性及其对下游基因的表达调控。通过稀疏优化模型预测增强子与靶基因的调控关系,进一步评估异常增强子对乳腺癌相关基因表达的影响。综合上述分析,本研究提供了一种新的分析流程,系统分析了乳腺癌相关增强子,发掘了乳腺癌增强子相关的非编码基因组突变、增强子和癌/抑癌基因之间的关联,有助于了解乳腺癌的发生发展机制,并提供潜在的治疗靶点。

Breast cancer is a major risk factor that threatens women′s health and lives.The activation of enhancers related to the development of cancer and cell pluripotency or the inactivation of enhancers that promote cell fate maintenance can lead to a"cell identity crisis",causing cells to become undifferentiated and even cancerous.Applying new bioinformatics methods,this study identified breast cancer-related enhancers and quantified enhancer RNA(eRNA)through in-depth analysis on breast cancer total RNA sequencing data of the cancer genome atlas(TCGA),explored the potential role of aberrant enhancers,and predicted their regulatory activities on target genes in breast cancer development and progression.Based on TCGA datasets,47921 eRNAs were identified in 112 pairs of tumor and adjacent samples,4830 of which had expression differences between tumor and adjacent samples.666 enhancer loci with eRNA expression differences overlapped with known breast cancer related genomic mutation sites.By computa-tionally analyzing the binding affinities of transcription factors on enhancers,it was found that some enhancer mutations may lead to changes in their binding affinity to transcription factors,thus affecting the activity of the enhancer and their ability to regulate down stream gene expression.The sparse optimization model was used to further predict the regulatory relationship between enhancers and their target genes known to play roles in breast cancer.In conclusion,this study provided a new analytic workflow to systematically analyze breast cancer related enhancers and explore the association among breast cancer related non-coding genomic mutations,enhancers and cancer/tumor suppressor genes,which is helpful to understand the mechanism of breast cancer occurrence and development,and provide potential therapeutic targets.