The landscape of antisense gene expression in human cancers

Abstract

High-throughput RNA sequencing has revealed more pervasive transcription of the human genome than previously anticipated. However, the extent of natural antisense transcripts' (NATs) expression, their regulation of cognate sense genes, and the role of NATs in cancer remain poorly understood. Here, we use strand-specific paired-end RNA sequencing (ssRNAseq) data from 376 cancer samples covering nine tissue types to comprehensively characterize the landscape of antisense expression. We found consistent antisense expression in at least 38% of annotated transcripts, which in general is positively correlated with sense gene expression. Investigation of sense/antisense pair expressions across tissue types revealed lineagespecific, ubiquitous and cancer-specific antisense loci transcription. Comparisons between tumor and normal samples identified both concordant (same direction) and discordant (opposite direction) sense/antisense expression patterns. Finally, we provide OncoNAT, a catalog of cancer-related genes with significant antisense transcription, which will enable future investigations of sense/antisense regulation in cancer. Using OncoNAT we identified several functional NATs, including NKX2-1-AS1 that regulates the NKX2-1 oncogene and cell proliferation in lung cancer cells. Overall, this study provides a comprehensive account of NATs and supports a role for NATs' regulation of tumor suppressors and oncogenes in cancer biology.

The Determinants of Directionality in Transcriptional Initiation

“…Secondary regulation may then generate a predominant direction of transcription either through pre- or post- initiation regulation. The fact that promoters can be unidirectional in some tissue types and bidirectional in others [22] supports the notion that core promoter sequences allow for bidirectional transcription but that this capacity is then regulated by secondary mechanisms such as cell-type specific TFs that promote either one or both transcripts in the pair in response to the different needs of the cell.…”

“…While the majority of PROMPTs are rapidly degraded, some stable noncoding transcripts produced from promoter regions have been shown to be functional [20, 21]. Some promoter transcripts are reproducibly observed in specific tissues, cell lineages, and cancers, while others are ubiquitous [22]. …”

“…Generally, eRNA transcription occurs bidirectionally, with both directions producing roughly equivalent levels of RNA [12]. In contrast, while it is likely that most promoters produce PROMPTs, or antisense transcripts, transcription is generally skewed towards the sense direction [22]. While depletion of exosome components leads to increases for both eRNAs and PROMPTs, eRNA increases are significantly higher [12].…”

The caste- and sex-specific DNA methylome of the termite Zootermopsis nevadensis

“…We first quantified the number of reads mapping to the sense and anti-sense direction of all gene models that did not overlap >50% of another gene mode. We then utilized a binomial-test to identify genes that were significantly transcribed from the antisense strand63. We then used a binomial test to assess the probability that a given locus in a given sample exhibited antisense transcription no different from that observed across all loci.…”

Dysregulation of miR-200 family microRNAs and epithelial-mesenchymal transition markers in oral squamous cell carcinoma

“…ZEB2 antisense RNA 1 (ZEB2-AS1) is an lncRNA that overlaps the 5' splice site of an intron within the 5' untranslated region (UTR) of the ZEB2 gene. ZEB2 and ZEB2-AS1 expressed as bidirectional cis-natural antisense transcripts (NAT) are essential in downregulating E-cadherin during EMT (15).…”