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Open Access Research

E2F mediates enhanced alternative polyadenylation in proliferation

Ran Elkon1, Jarno Drost1, Gijs van Haaften1, Mathias Jenal1, Mariette Schrier1, Joachim AF Oude Vrielink1 and Reuven Agami12*

  • * Corresponding author: Reuven Agami r.agami@nki.nl

  • † Equal contributors

Author affiliations

1 Division of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands

2 The Centre for Biomedical Genetics, UMCU, Stratenum 3.217, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands

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Citation and License

Genome Biology 2012, 13:R59  doi:10.1186/gb-2012-13-7-r59

Published: 2 July 2012

Abstract

Background

The majority of mammalian genes contain multiple poly(A) sites in their 3' UTRs. Alternative cleavage and polyadenylation are emerging as an important layer of gene regulation as they generate transcript isoforms that differ in their 3' UTRs, thereby modulating genes' response to 3' UTR-mediated regulation. Enhanced cleavage at 3' UTR proximal poly(A) sites resulting in global 3' UTR shortening was recently linked to proliferation and cancer. However, mechanisms that regulate this enhanced alternative polyadenylation are unknown.

Results

Here, we explored, on a transcriptome-wide scale, alternative polyadenylation events associated with cellular proliferation and neoplastic transformation. We applied a deep-sequencing technique for identification and quantification of poly(A) sites to two human cellular models, each examined under proliferative, arrested and transformed states. In both cell systems we observed global 3' UTR shortening associated with proliferation, a link that was markedly stronger than the association with transformation. Furthermore, we found that proliferation is also associated with enhanced cleavage at intronic poly(A) sites. Last, we found that the expression level of the set of genes that encode for 3'-end processing proteins is globally elevated in proliferation, and that E2F transcription factors contribute to this regulation.

Conclusions

Our results comprehensively identify alternative polyadenylation events associated with cellular proliferation and transformation, and demonstrate that the enhanced alternative polyadenylation in proliferative conditions results not only in global 3' UTR shortening but also in enhanced premature cleavage in introns. Our results also indicate that E2F-mediated co-transcriptional regulation of 3'-end processing genes is one of the mechanisms that links enhanced alternative polyadenylation to proliferation.