de Langen Pierre, Hammal Fayrouz, Guéret Elise, Mouren Jean-Christophe, Spinelli Lionel, Ballester Benoit
Aix Marseille Univ, INSERM, TAGC, Marseille, France.
Cell Genom. 2023 Sep 29;3(10):100411. doi: 10.1016/j.xgen.2023.100411. eCollection 2023 Oct 11.
Intergenic transcription in normal and cancerous tissues is pervasive but incompletely understood. To investigate this, we constructed an atlas of over 180,000 consensus RNA polymerase II (RNAPII)-bound intergenic regions from 900 RNAPII chromatin immunoprecipitation sequencing (ChIP-seq) experiments in normal and cancer samples. Through unsupervised analysis, we identified 51 RNAPII consensus clusters, many of which mapped to specific biotypes and revealed tissue-specific regulatory signatures. We developed a meta-clustering methodology to integrate our RNAPII atlas with active transcription across 28,797 RNA sequencing (RNA-seq) samples from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Encyclopedia of DNA Elements (ENCODE). This analysis revealed strong tissue- and disease-specific interconnections between RNAPII occupancy and transcriptional activity. We demonstrate that intergenic transcription at RNAPII-bound regions is a novel per-cancer and pan-cancer biomarker. This biomarker displays genomic and clinically relevant characteristics, distinguishing cancer subtypes and linking to overall survival. Our results demonstrate the effectiveness of coherent data integration to uncover intergenic transcriptional activity in normal and cancer tissues.
正常组织和癌组织中的基因间转录普遍存在，但尚未完全了解。为了对此进行研究，我们构建了一个图谱，该图谱包含来自正常样本和癌症样本的900个RNA聚合酶II（RNAPII）染色质免疫沉淀测序（ChIP-seq）实验中超过180,000个一致的RNAPII结合基因间区域。通过无监督分析，我们鉴定出51个RNAPII一致簇，其中许多映射到特定的生物类型，并揭示了组织特异性调控特征。我们开发了一种元聚类方法，将我们的RNAPII图谱与来自癌症基因组图谱（TCGA）、基因型-组织表达（GTEx）和DNA元件百科全书（ENCODE）的28,797个RNA测序（RNA-seq）样本中的活跃转录进行整合。该分析揭示了RNAPII占据与转录活性之间强烈的组织和疾病特异性相互联系。我们证明，RNAPII结合区域的基因间转录是一种新的癌症特异性和泛癌症生物标志物。这种生物标志物显示出基因组和临床相关特征，可区分癌症亚型并与总生存期相关联。我们的结果证明了连贯数据整合在揭示正常组织和癌组织中基因间转录活性方面的有效性。
