An integrative model for alternative polyadenylation, IntMAP, delineates mTOR-modulated endoplasmic reticulum stress response

Jae Woong Chang, Wei Zhang, Hsin Sung Yeh, Meeyeon Park, Chengguo Yao, Yongsheng Shi, Rui Kuang, Jeongsik Yong

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

3′-untranslated regions (UTRs) can vary through the use of alternative polyadenylation sites during pre-mRNA processing. Multiple publically available pipelines combining high profiling technologies and bioinformatics tools have been developed to catalog changes in 3′-UTR lengths. In our recent RNA-seq experiments using cells with hyper-activated mammalian target of rapamycin (mTOR), we found that cellular mTOR activation leads to transcriptome-wide alternative polyadenylation (APA), resulting in the activation of multiple cellular pathways. Here, we developed a novel bioinformatics algorithm, IntMAP, which integrates RNA-Seq and PolyA Site (PAS)-Seq data for a comprehensive characterization of APA events. By applying IntMAP to the datasets from cells with hyper-activated mTOR, we identified novel APA events that could otherwise not be identified by either profiling method alone. Several transcription factors including Cebpg (CCAAT/enhancer binding protein gamma) were among the newly discovered APA transcripts, indicating that diverse transcriptional networks may be regulated by mTOR-coordinated APA. The prevention of APA in Cebpg using the CRISPR/cas9-mediated genome editing tool showed that mTOR-driven 3′-UTR shortening in Cebpg is critical in protecting cells from endoplasmic reticulum (ER) stress. Taken together, we present IntMAP as a new bioinformatics algorithm for APA analysis by which we expand our understanding of the physiological role of mTOR-coordinated APA events to ER stress response. IntMAP toolbox is available at http://compbio.cs.umn.edu/IntMAP/.

Original languageEnglish (US)
Pages (from-to)5996-6008
Number of pages13
JournalNucleic acids research
Volume46
Issue number12
DOIs
StatePublished - Jul 6 2018

Bibliographical note

Funding Information:
National Institutes of Health [1R01GM113952-01A1]; Department of Defense – Congressionally Directed Medical Research Programs [W81XWH-16-1-0135 to J.Y.]. Funding for open access charge: Department of Defense-Congressionally Directed Medical Research Programs. Conflict of interest statement. None declared.

Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research.

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