RT Journal Article
SR Electronic
T1 A pan cancer analysis of promoter activity highlights the regulatory role of alternative transcription start sites and their association with noncoding mutations
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 176487
DO 10.1101/176487
A1 Deniz Demircioğlu
A1 Martin Kindermans
A1 Tannistha Nandi
A1 Engin Cukuroglu
A1 Claudia Calabrese
A1 Nuno A. Fonseca
A1 Andre Kahles
A1 Kjong Lehmann
A1 Oliver Stegle
A1 PCAWG-3
A1 PCAWG-Network
A1 Alvis Brazma
A1 Angela Brooks
A1 Gunnar Rätsch
A1 Patrick Tan
A1 Jonathan Göke
YR 2017
UL http://biorxiv.org/content/early/2017/08/15/176487.abstract
AB Most human protein-coding genes are regulated by multiple, distinct promoters, suggesting that the choice of promoter is as important as its level of transcriptional activity. While the role of promoters as driver elements in cancer has been recognized, the contribution of alternative promoters to regulation of the cancer transcriptome remains largely unexplored. Here we show that active promoters can be identified using RNA-Seq data, enabling the analysis of promoter activity in more than 1,000 cancer samples with matched whole genome sequencing data. We find that alternative promoters are a major contributor to tissue-specific regulation of isoform expression and that alternative promoters are frequently deregulated in cancer, affecting known cancer-genes and novel candidates. Noncoding passenger mutations are enriched at promoters of genes with lower regulatory complexity, whereas noncoding driver mutations occur at genes with multiple promoters, often affecting the promoter that shows the highest level of activity. Together our study demonstrates that the landscape of active promoters shapes the cancer transcriptome, opening many opportunities to further explore the interplay of regulatory mechanism and noncoding somatic mutations with transcriptional aberrations in cancer.