Journal
FASEB JOURNAL
Volume 28, Issue 4, Pages 1870-1879Publisher
WILEY
DOI: 10.1096/fj.13-245522
Keywords
transcriptional regulation; in vivo assessment; natriuretic peptide
Categories
Funding
- Japan Society for the Promotion of Science (JSPS) through the Funding Program for Next Generation World-Leading Researchers (NEXT Program)
- Council for Science and Technology Policy (CSTP)
- Ministry of Health, Labor, and Welfare of Japan
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Japan Society for the Promotion of Science
- Japan Heart Foundation
- Japan Cardiovascular Research Foundation
- Japan Medical Association
- Japan Intractable Diseases Research Foundation
- Uehara Memorial Foundation
- Takeda Science Foundation
- Ichiro Kanehara Foundation
- Inoue Foundation for Science
- Mochida Memorial Foundation
- Heart Foundation/Novartis Grant for Research Award on Molecular and Cellular Cardiology
- Japan Foundation of Applied Enzymology
- Naito Foundation
- Banyu Foundation
- Showa Houkoukai
- Grants-in-Aid for Scientific Research [25118709, 25860599, 24790757] Funding Source: KAKEN
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Recent advances in genome analysis have enabled the identification of numerous distal enhancers that regulate gene expression in various conditions. However, the enhancers involved in pathological conditions are largely unknown because of the lack of in vivo quantitative assessment of enhancer activity in live animals. Here, we established a noninvasive and quantitative live imaging system for monitoring transcriptional activity and identified a novel stress-responsive enhancer of Nppa and Nppb, the most common markers of heart failure. The enhancer is a 650-bp fragment within 50 kb of the Nppa and Nppb loci. A chromosome conformation capture (3C) assay revealed that this distal enhancer directly interacts with the 5 '-flanking regions of Nppa and Nppb. To monitor the enhancer activity in a live heart, we established an imaging system using the firefly luciferase reporter. Using this imaging system, we observed that the novel enhancer activated the reporter gene in pressure overload-induced failing hearts (failing hearts: 5.7 +/- 1.3-fold; sham-surgery hearts: 1.0 +/- 0.2-fold; P < 0.001, repeated-measures ANOVA). This method will be particularly useful for identifying enhancers that function only during pathological conditions.-Matsuoka, K., Asano, Y., Higo, S., Tsukamoto, O., Yan, Y., Yamazaki, S., Matsuzaki, T., Kioka, H., Kato, H., Uno, Y., Asakura, M., Asanuma, H., Minamino, T., Aburatani, H., Kitakaze, M., Komuro, I., and Takashima, S. Noninvasive and quantitative live imaging reveals a potential stress-responsive enhancer in the failing heart.
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