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Cell Chem Biol. 2018 Dec 20;25(12):1470-1484.e5. doi: 10.1016/j.chembiol.2018.09.006. Epub 2018 Oct 4.

Decoding Transcriptome Dynamics of Genome-Encoded Polyadenylation and Autoregulation with Small-Molecule Modulators of Alternative Polyadenylation.

Author information

1
Research Department, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: shinsuke.araki@takeda.com.
2
Research Department, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
3
Molecular Oncology, BC Cancer Agency, 675 W 10th Avenue, Vancouver, BC V5Z 1L3, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada. Electronic address: saparicio@bccrc.ca.

Abstract

Alternative polyadenylation (APA) plays a critical role in regulating gene expression. However, the balance between genome-encoded APA processing and autoregulation by APA modulating RNA binding protein (RBP) factors is not well understood. We discovered two potent small-molecule modulators of APA (T4 and T5) that promote distal-to-proximal (DtoP) APA usage in multiple transcripts. Monotonically responsive APA events, induced by short exposure to T4 or T5, were defined in the transcriptome, allowing clear isolation of the genomic sequence features and RBP motifs associated with DtoP regulation. We found that longer vulnerable introns, enriched with distinctive A-rich motifs, were preferentially affected by DtoP APA, thus defining a core set of genes with genomically encoded DtoP regulation. Through APA response pattern and compound-small interfering RNA epistasis analysis of APA-associated RBP factors, we further demonstrated that DtoP APA usage is partly modulated by altered autoregulation of polyadenylate binding nuclear protein-1 signaling.

KEYWORDS:

PABPN1; RNA binding protein; alternative polyadenylation; alternative polyadenylation modulator; autoregulation; reporter screening

PMID:
30293940
DOI:
10.1016/j.chembiol.2018.09.006
[Indexed for MEDLINE]

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