Regulation of Alternative Polyadenylation by Nkx2-5 and Xrn2 During Mouse Heart Development

Overview

Journal Elife

Specialty Biology

Date 2016 Jun 23

PMID 27331609

Citations 13

Authors

Keisuke Nimura

Masamichi Yamamoto

Makiko Takeichi

Kotaro Saga

Katsuyoshi Takaoka

Norihiko Kawamura

Hirohisa Nitta

Hiromichi Nagano

Saki Ishino

Tatsuya Tanaka

Robert J Schwartz

Hiroyuki Aburatani

Yasufumi Kaneda

Affiliations

Soon will be listed here.

Abstract

Transcription factors organize gene expression profiles by regulating promoter activity. However, the role of transcription factors after transcription initiation is poorly understood. Here, we show that the homeoprotein Nkx2-5 and the 5'-3' exonuclease Xrn2 are involved in the regulation of alternative polyadenylation (APA) during mouse heart development. Nkx2-5 occupied not only the transcription start sites (TSSs) but also the downstream regions of genes, serving to connect these regions in primary embryonic cardiomyocytes (eCMs). Nkx2-5 deficiency affected Xrn2 binding to target loci and resulted in increases in RNA polymerase II (RNAPII) occupancy and in the expression of mRNAs with long 3'untranslated regions (3' UTRs) from genes related to heart development. siRNA-mediated suppression of Nkx2-5 and Xrn2 led to heart looping anomaly. Moreover, Nkx2-5 genetically interacts with Xrn2 because Nkx2-5(+/-)Xrn2(+/-), but neither Nkx2-5(+/-)nor Xrn2(+/-), newborns exhibited a defect in ventricular septum formation, suggesting that the association between Nkx2-5 and Xrn2 is essential for heart development. Our results indicate that Nkx2-5 regulates not only the initiation but also the usage of poly(A) sites during heart development. Our findings suggest that tissue-specific transcription factors is involved in the regulation of APA.

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