A Pan-cancer Transcriptome Analysis Reveals Pervasive Regulation through Alternative Promoters

Abstract

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. However, while a global change in transcription is recognized as a defining feature of cancer, the contribution of alternative promoters still remains largely unexplored. Here, we infer active promoters using RNA-seq data from 18,468 cancer and normal samples, demonstrating that alternative promoters are a major contributor to context-specific regulation of transcription. We find that promoters are deregulated across tissues, cancer types, and patients, affecting known cancer genes and novel candidates. For genes with independently regulated promoters, we demonstrate that promoter activity provides a more accurate predictor of patient survival than gene expression. Our study suggests that a dynamic landscape of active promoters shapes the cancer transcriptome, opening new diagnostic avenues and opportunities to further explore the interplay of regulatory mechanisms with transcriptional aberrations in cancer. 3 rd ≥4 th Rank of correlation (Spearman) Mean promoter activity (RNA-Seq) Mean log H3K4me3 (ChIP-Seq) read count Adrenal Gland Arterial Blood Vessel Blood Blood Vessel Brain

LARP1 isoform expression in human cancer cell lines

“…Our findings support a recently published study predicting over 10 potential alternative promoters for LARP1 [28] and are consistent with evidence that most coding genes have multiple isoforms but only one expressed protein [9]. Whilst the evolutionary conservation of an expressed isoform indicates it has a conserved biological function [29], the role of non-expressed isoforms remains controversial [9,30].…”

Comprehensive characterization of single cell full-length isoforms in human and mouse with long-read sequencing

“…Alternative promoters have been shown to regulate cancer-specific transcription 27 . Here we found transcripts with different TSSs expressed in different cancer cell lines.…”

Cancer Epigenomics and Beyond: Advancing the Precision Oncology Paradigm

“…Subsequently, an extensive in silico interrogation of large transcriptomic datasets of .18,000 samples covering 42 cancer types showed that alternative promoter switching is pervasive, tissue specific, and correlative with survival. [122] These studies illustrate how tumor epigenetic states can significantly increase RNA isoform diversity from the same DNA template without obligate sequence mutations. In turn, the greater complexity in RNAs can create or expand the repertoire of tumor survival pathways.…”

“…Global epigenomic and transcriptomic profiles of tumors are dominated by gene programs that reflect the normal tissues from which they originate. [122,129] Maintenance of cell identify-of both normal and malignant phenotypes-during and immediately after mitosis has been shown to be mediated by epigenetic mechanisms that act on specific chromatin loci, a process called mitotic gene bookmarking. [130] Hence, neoplastic transformation and tumor dedifferentiation are likely sequelae of epigenetic aberrations coupled to genomic instability in a vicious cycle.…”