PMID- 27331609
OWN - NLM
STAT- MEDLINE
DCOM- 20171113
LR  - 20181113
IS  - 2050-084X (Electronic)
IS  - 2050-084X (Linking)
VI  - 5
DP  - 2016 Jun 22
TI  - Regulation of alternative polyadenylation by Nkx2-5 and Xrn2 during mouse heart 
      development.
LID - e16030 [pii]
LID - 10.7554/eLife.16030 [doi]
AB  - 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.
FAU - Nimura, Keisuke
AU  - Nimura K
AUID- ORCID: 0000-0001-9680-2646
AD  - Division of Gene Therapy Science, Osaka University Graduate School of Medicine, 
      Suita, Japan.
FAU - Yamamoto, Masamichi
AU  - Yamamoto M
AD  - Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, 
      Japan.
FAU - Takeichi, Makiko
AU  - Takeichi M
AD  - Division of Gene Therapy Science, Osaka University Graduate School of Medicine, 
      Suita, Japan.
FAU - Saga, Kotaro
AU  - Saga K
AD  - Division of Gene Therapy Science, Osaka University Graduate School of Medicine, 
      Suita, Japan.
FAU - Takaoka, Katsuyoshi
AU  - Takaoka K
AD  - Developmental Genetics Group, Graduate School of Frontier Biosciences, Osaka 
      University, Suita, Japan.
FAU - Kawamura, Norihiko
AU  - Kawamura N
AD  - Division of Gene Therapy Science, Osaka University Graduate School of Medicine, 
      Suita, Japan.
AD  - Department of Urology, Osaka University Graduate School of Medicine, Suita, 
      Japan.
FAU - Nitta, Hirohisa
AU  - Nitta H
AD  - Division of Gene Therapy Science, Osaka University Graduate School of Medicine, 
      Suita, Japan.
FAU - Nagano, Hiromichi
AU  - Nagano H
AD  - Division of Gene Therapy Science, Osaka University Graduate School of Medicine, 
      Suita, Japan.
FAU - Ishino, Saki
AU  - Ishino S
AD  - Center for Medical Research and Education, Osaka University Graduate School of 
      Medicine, Suita, Japan.
FAU - Tanaka, Tatsuya
AU  - Tanaka T
AD  - Center for Medical Research and Education, Osaka University Graduate School of 
      Medicine, Suita, Japan.
FAU - Schwartz, Robert J
AU  - Schwartz RJ
AD  - Department of Biology and Biochemistry, University of Houston, Houston, Unites 
      States.
FAU - Aburatani, Hiroyuki
AU  - Aburatani H
AD  - Genome Science Division, Research Center for Advanced Science and Technology 
      (RCAST), The University of Tokyo, Tokyo, Japan.
FAU - Kaneda, Yasufumi
AU  - Kaneda Y
AD  - Division of Gene Therapy Science, Osaka University Graduate School of Medicine, 
      Suita, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160622
PL  - England
TA  - Elife
JT  - eLife
JID - 101579614
RN  - 0 (Homeobox Protein Nkx-2.5)
RN  - 0 (Nkx2-5 protein, mouse)
RN  - EC 3.1.- (Exoribonucleases)
RN  - EC 3.1.11.- (Xrn2 protein, mouse)
SB  - IM
MH  - Animals
MH  - Exoribonucleases/genetics/*metabolism
MH  - *Gene Expression Regulation, Developmental
MH  - Heart/*embryology
MH  - Homeobox Protein Nkx-2.5/genetics/*metabolism
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - *Polyadenylation
PMC - PMC4982761
OTO - NOTNLM
OT  - chromosomes
OT  - development
OT  - gene expression
OT  - genes
OT  - mouse
OT  - transcription factors
COIS- The authors declare that no competing interests exist.
EDAT- 2016/06/23 06:00
MHDA- 2017/11/14 06:00
PMCR- 2016/06/23
CRDT- 2016/06/23 06:00
PHST- 2016/03/14 00:00 [received]
PHST- 2016/06/21 00:00 [accepted]
PHST- 2016/06/23 06:00 [entrez]
PHST- 2016/06/23 06:00 [pubmed]
PHST- 2017/11/14 06:00 [medline]
PHST- 2016/06/23 00:00 [pmc-release]
AID - e16030 [pii]
AID - 16030 [pii]
AID - 10.7554/eLife.16030 [doi]
PST - epublish
SO  - Elife. 2016 Jun 22;5:e16030. doi: 10.7554/eLife.16030.