| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2012: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
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| Research Abstract |
Mammalian hearts have been limited their regenerative capacity, whereas fishes and amphibians keep high plasticity even in the adult. However, no factors have been reported as key factors for cardiac regeneration between mammalians and fishes. Recently, several epigenetic factors with specific roles in cardiogenesis have been reported. Especially, Brg1-BAF60c, main component in SWI/SNF chromatin remodelling complexes play as key factors for cardiomyocyte induction or differentiation (Takeuchi&Bruneau, Nature 2009; Takeuchi et al., Nature Commun2011). Interestingly, Baf60c expression in the ventricle heart was completelydisappeared by postnatal 7 days (P7D) after birth. This line is so consistent withheart regeneration capacity in mammals, reported by Porrello et al. (Science 2011), suggesting that epigenetic molecules might be profoundly associated with mammalian heart regenerative capacity.To address the questions whether cardiac-Baf core component, Baf60c, acts as anearly response fa
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ctor during heart regeneration or not, two animal models (axolotls for regenerative animals and mice for limited regenerative animals) were utilized. Baf60c mRNA and its protein were strongly up-regulated within 12 hours after heart resection in both axolotl and neonatal (P2D) mice, and their expression were maintained in both animals during heart regeneration. Interestingly, postnatal 3 weeks-mouse heart with Baf60c viral infection after resection keeps its regeneration capacity. BAF-TG mice in 8 weeks-adult, which was generated for stable expression of Baf60c in cardiomyocytes in adults, protected fibrosis post myocardial infarction (MI), following that heart function was recovered by 4 weeks.In vivo ChIP analyses have revealed that chromatin conformation in viralinfected-heart and BAF-TG hearts in adult mice was dramatically arranged. Brg1 directly binds on several cardiac fetal genes’ promoters and regulates their expression levels in Baf60c dependent manner. Surprisingly, major cardiac fetal and angiogenesis gene promoters in the Baf60c-infected heart and BAF-TG heart in adults were still opened, accordingly with remodelling of histone H3K4 or H3K9 methylated-modification enzymes, DNA-methylated enzymes, HDACs and NurD components on these promoters.These data indicated that chromatin-histone conformation change should benecessary for heart regeneration. In this session, we would like to show genome-wide analyses for understanding the mechanism of chromatin-histone regulation in heartplasticity and heart failure. Less
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