Regulation of alternative polyadenylation by Nkx2-5 and Xrn2 during mouse heart development

被引：19

作者：

Nimura, Keisuke ^{[1
]}

Yamamoto, Masamichi ^{[2
]}

Takeichi, Makiko ^{[1
]}

Saga, Kotaro ^{[1
]}

Takaoka, Katsuyoshi ^{[3
]}

Kawamura, Norihiko ^{[1
,4
]}

Nitta, Hirohisa ^{[1
]}

Nagano, Hiromichi ^{[1
]}

Ishino, Saki ^{[5
]}

Tanaka, Tatsuya ^{[5
]}

Schwartz, Robert J. ^{[6
]}

Aburatani, Hiroyuki ^{[7
]}

Kaneda, Yasufumi ^{[1
]}

机构：

[1] Osaka Univ, Grad Sch Med, Div Gene Therapy Sci, 2-2 Yamada Oka, Suita, Osaka 5650871, Japan

[2] Kyoto Univ, Dept Nephrol, Grad Sch Med, Sakyo Ku, Shogoin Kawahara Cho 54, Kyoto 6068507, Japan

[3] Osaka Univ, Grad Sch Frontier Biosci, Dev Genet Grp, 1-3 Yamada Oka, Suita, Osaka 5650871, Japan

[4] Osaka Univ, Grad Sch Med, Dept Urol, Suita, Osaka 5650871, Japan

[5] Osaka Univ, Ctr Med Res & Educ, Grad Sch Med, 2-2 Yamada Oka, Suita, Osaka 5650871, Japan

[6] Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA

[7] Univ Tokyo, Genome Sci Div, RCAST, Tokyo 1538904, Japan

来源：

ELIFE | 2016年 / 5卷

关键词：

heart development; Nkx2-5; Xrn2; alternative polyadenylation; transcription; RNA-POLYMERASE-II; PROMOTES TRANSCRIPTION TERMINATION; LEFT-RIGHT ASYMMETRY; LARGE GENE LISTS; HOMEOBOX GENE; HUMAN GENOME; CHROMATIN; EXPRESSION; MICE; WIDESPREAD;

D O I：

10.7554/eLife.16030

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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(+/-) 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 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

引用

页数：62

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