Chen Yunqin, Li Hong, Li Yuan-Yuan, Li Yixue
School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Front Genet. 2021 Jan 7;11:560997. doi: 10.3389/fgene.2020.560997. eCollection 2020.
Head-to-Head (H2H) gene pairs are regulated by bidirectional promoters and divergently transcribed from opposite DNA strands with transcription start sites (TSSs) separated within 1 kb. H2H organization is ancient and conserved, and H2H pairs tend to exhibit similar expression patterns. Although some H2H genes have been reported to be associated with disease and cancer, there is a lack of systematic studies on H2H organization in the scenario of cancer development.
Human H2H gene pairs were identified based on GENCODE hg19 and the functional relevance of H2H pairs was explored through function enrichment and semantic similarity analysis. To investigate the association between H2H organization and carcinogenesis, pan-cancer differential analysis of H2H genes about transcriptional activity, co-expression and transcriptional regulation by transcription factors and enhancers were performed based on data from The Cancer Genome Atlas. Cox proportional hazards regression model and log-rank test were used to determine the prognostic powers of H2H pairs.
In the present study, we first updated H2H genes from 1,447 to 3,150 pairs, from which the peak group with TSS distance of 1-100 was observed as expected in our previous work. It was found that housekeeping genes, mitochondrial-functional associated genes and cancer genes tend to be organized in H2H arrangement. Pan-cancer analysis indicates that H2H genes are transcriptionally active than random genes in both normal and cancer tissues, but H2H pairs display higher correlation in cancer than in normal. Particularly, housekeeping H2H pairs are differentially correlated much more significantly than non-housekeeping H2H pairs are. Some of differentially correlated H2H pairs were found to be associated with prognosis. The alteration of TF similarity seems to contribute to differential co-expression of H2H pairs during carcinogenesis; meanwhile remote enhancers also at least partly explain the differential co-expression and co-regulation of H2H pairs.
H2H pairs tend to show much stronger positive expression correlation in cancer than in normal due to differential regulation of bidirectional promoters. The study provides insights into the significance of H2H organization in carcinogenesis and the underlying dysfunctional regulation mechanisms. Those differentially correlated H2H pairs associated with survival have the potential to be prognostic biomarkers and therapeutic targets for cancer.
头对头（H2H）基因对由双向启动子调控，从相反的DNA链反向转录，转录起始位点（TSS）相距在1 kb以内。H2H结构古老且保守，H2H基因对往往表现出相似的表达模式。尽管已有报道称一些H2H基因与疾病和癌症相关，但在癌症发生发展的背景下，缺乏对H2H结构的系统性研究。
基于GENCODE hg19鉴定人类H2H基因对，并通过功能富集和语义相似性分析探索H2H基因对的功能相关性。为研究H2H结构与致癌作用之间的关联，基于癌症基因组图谱（The Cancer Genome Atlas）的数据，对H2H基因在转录活性、共表达以及转录因子和增强子的转录调控方面进行泛癌差异分析。使用Cox比例风险回归模型和对数秩检验来确定H2H基因对的预后能力。
在本研究中，我们首先将H2H基因从1447对更新至3150对，正如我们之前工作所预期的那样，观察到TSS距离为1 - 100的峰值组。发现管家基因、线粒体功能相关基因和癌症基因倾向于以H2H排列方式存在。泛癌分析表明，在正常组织和癌组织中，H2H基因比随机基因具有更高的转录活性，但H2H基因对比正常组织中的基因对在癌症中显示出更高的相关性。特别是，管家H2H基因对比非管家H2H基因对的差异相关性更为显著。发现一些差异相关的H2H基因对与预后相关。转录因子相似性的改变似乎有助于致癌过程中H2H基因对的差异共表达；同时，远距离增强子也至少部分解释了H2H基因对的差异共表达和共调控。
由于双向启动子的差异调控，H2H基因对比正常组织在癌症中往往表现出更强的正表达相关性。该研究为H2H结构在致癌作用中的意义以及潜在的功能失调调控机制提供了见解。那些与生存相关的差异相关H2H基因对有可能成为癌症的预后生物标志物和治疗靶点。
