Antisense transcription regulates the expression of sense gene via alternative polyadenylation

Ting Shen,Ting Ni,Huan Li,Jun Yao,Yifan Song,Miao Han,Gang Wei,Ming Yu

doi:10.1007/s13238-017-0497-0

Ting Shen, Ting Ni + Show 6 more

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https://doi.org/10.1007/s13238-017-0497-0

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Abstract

Natural antisense transcripts (NAT) and alternative polyadenylation (APA) of messenger RNA (mRNA) are important contributors of transcriptome complexity, each playing a critical role in multiple biological processes. However, whether they have crosstalk and function collaboratively is unclear. We discovered that APA enriched in human sense-antisense (S-AS) gene pairs, and finally focused on RNASEH2C-KAT5 S-AS pair for further study. In cis but not in trans over-expression of the antisense KAT5 gene promoted the usage of distal polyA (pA) site in sense gene RNASEH2C, which generated longer 3′ untranslated region (3′UTR) and produced less protein, accompanying with slowed cell growth. Mechanistically, elevated Pol II occupancy coupled with SRSF3 could explain the higher usage of distal pA site. Finally, NAT-mediated downregulation of sense gene’s protein level in RNASEH2C-KAT5 pair was specific for human rather than mouse, which lacks the distal pA site of RNASEH2C. We provided the first evidence to support that certain gene affected phenotype may not by the protein of its own, but by affecting the expression of its overlapped gene through APA, implying an unexpected view for understanding the link between genotype and phenotype.

Highlights

Eukaryotic transcriptome has exhibited increasing complexity due to the discovery of gene regulation at multiple aspects (Licatalosi and Darnell, 2010), such as dynamic variation in transcription initiation, alternative splicing, alternative 3′ end processing and RNA localization, etc
Tail-to-tail S-AS gene pairs were chosen for further study since they overlapped in the polyadenylation sites and more likely to have mechanistic interaction between antisense transcription and alternative polyadenylation (APA)
Since distal polyA site of one gene in tail-to-tail S-AS gene pair always stayed on the way of the transcription of the other gene, we examined the correlation between change of Natural antisense transcripts (NAT) expression and the distal pA site usage of the sense gene by PA-seq, which can quantify both the distal/proximal pA site usage and the relative gene expression level (Ni et al, 2013)

Summary

Introduction

Eukaryotic transcriptome has exhibited increasing complexity due to the discovery of gene regulation at multiple aspects (Licatalosi and Darnell, 2010), such as dynamic variation in transcription initiation, alternative splicing, alternative 3′ end processing and RNA localization, etc. There exist many gene loci characterized with sense and overlapping natural antisense transcripts (NATs) in many species (Katayama et al, 2005; Yelin et al, 2003; David et al, 2006). In S-AS gene pairs, sense gene usually refers to the protein-coding gene, while the antisense partner can be either coding or non-coding. NATs can affect the expression of corresponding sense genes in cis or in trans at multiple levels (Pelechano and Steinmetz, 2013). One possible mechanism is that NATs can act as a scaffolder to recruit trans-factors to the sense gene loci, and affect its transcription by changing locally the state of DNA methylation or histone modification (Pelechano and Steinmetz, 2013). A recent study reported that an antisense transcript, 5S-OT, modulated alternative splicing in trans through Alu or anti-Alu

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