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"A Study of MicroRNA-98 and MicroRNA-206 in the Heart: Their Regulation and Function in Cardiac Myocytes Growth and Death"

by
Yanfei Yang
Cell Biology and Molecular Medicine Program
B.S. 2005, University of Science and Technology of China



Thesis Advisor: Junichi Sadoshima, M.D., Ph.D.
Professor
Department of Cell Biology and Molecular Medicine

Tuesday, December 6, 2011
12:00 P.M., MSB G609


Abstract

I. Thioredoxin1 (Trx1) negatively regulates Angiotensin II (AngII)-induced cardiac hypertrophy through upregulation of microRNA-98 (miR-98).
We investigated the role of microRNAs in mediating the anti-hypertrophic effect of Trx1 upon AngII-induced cardiac hypertrophy (AICH). Microarray and qRT-PCR/Northern blot analyses showed that Trx1 upregulates members of the let-7 family, including miR-98, in the heart and the cardiomyocytes (CMs). miR-98 reduced cell size both at baseline and in response to AngII in CMs. Knock-down of miR-98, and of other members of the let-7 family, augmented AICH and attenuated Trx1-mediated inhibition of AICH, suggesting that endogenous miR-98/let-7 mediates the anti-hypertrophic effect of Trx1. Cyclin D2 is one of the predicted targets of miR-98. AngII upregulated cyclin D2, which in turn mediates AICH, whereas Trx1 inhibited AngII-induced upregulation of cyclin D2. miR-98 decreased both expression of cyclin D2 and the activity of a cyclin D2 3’UTR luciferase reporter, suggesting that both Trx1 and miR-98 negatively regulate cyclin D2. Overexpression of cyclin D2 attenuated the suppression of AICH by miR-98. These results suggest that Trx1 upregulates expression of the let-7 family, including miR-98, which in turn inhibits cardiac hypertrophy, in part through downregulation of cyclin D2.

II. MiR-206 mediates YAP-induced cardiac hypertrophy and survival.
The Drosophila Hippo regulates apoptosis and proliferation through suppression of Yorkie, a transcription co-factor, and Yorkie upregulates bantam, a microRNA. YAP, a mammalian homologue of Yorkie, stimulates hypertrophy and inhibits apoptosis in CMs. We identified miR-206 as a mammalian homologue of bantam. miRNA microarray analyses, qRT-PCR, Northern blot and miRNA enhancer luciferase assays showed that miR-206 is upregulated by YAP in CMs. miR-206 and miR-1 are homologous muscle-specific microRNAs. Upregulation of miR-1 or miR-1 enhancer by YAP was not significant. miR-206 induced cardiac hypertrophy (CH) both in vitro and in vivo. However, miR-1 inhibited CH. In contrast to miR-1, which induced cell death, miR-206 inhibited cardiac cell death. Downregulation of miR-206 attenuated YAP-induced CH and survival; while downregulation of miR-1 tended to exaggerate YAP-induced CH, indicating miR-206, not miR-1, mediates YAP-induced CH and survival. FoxP1 is one of the predicted targets of miR-206. miR-206 decreased both FoxP1 expression and FoxP1 3’UTR luciferase reporter activity, which is distinct than miR-1. Overexpression of FoxP1 attenuated both YAP and miR-206-induced CH and survival. In summary, YAP upregulates miR-206, which in turn mediates hypertrophy and survival through downregulation of FoxP1 in CMs. miR-206, distinct from miR-1, mimics the function of Drosophila bantam.


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