William W Du1,2, Weining Yang1, Yu Chen3, Zhong-Kai Wu3, Francis Stuart Foster1, Zhenguo Yang1,2, Xiangmin Li1,2,4, Burton B Yang1,2,5. 1. Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada. 2. Department of Laboratory Medicine and Pathobiology, University of Toronto, S-Wing Research Building, 2075 Bayview Ave, Toronto M4N 3M5, Canada. 3. 2nd Department of Cardiac Surgery, The First Hospital, Sun Yet-Sen University, Guangzhou, China. 4. State Key Laboratory of Applied Microbiology Southern China (The Ministry-Province Joint Development), Guangdong Institute of Microbiology, Guangzhou 510070, PR China. 5. Institute of Medical Science, University of Toronto, Toronto, Canada.
Abstract
AIMS: Circular RNAs are a subclass of non-coding RNAs detected within mammalian cells. This study was designed to test the roles of a circular RNA circ-Foxo3 in senescence using in vitro and in vivo approaches. METHODS AND RESULTS: Using the approaches of molecular and cellular biology, we show that a circular RNA generated from a member of the forkhead family of transcription factors, Foxo3, namely circ-Foxo3, was highly expressed in heart samples of aged patients and mice, which was correlated with markers of cellular senescence. Doxorubicin-induced cardiomyopathy was aggravated by ectopic expression of circ-Foxo3 but was relieved by silencing endogenous circ-Foxo3. We also found that silencing circ-Foxo3 inhibited senescence of mouse embryonic fibroblasts and that ectopic expression of circ-Foxo3 induced senescence. We found that circ-Foxo3 was mainly distributed in the cytoplasm, where it interacted with the anti-senescent protein ID-1 and the transcription factor E2F1, as well as the anti-stress proteins FAK and HIF1α. CONCLUSION: We conclude that ID-1, E2F1, FAK, and HIF1α interact with circ-Foxo3 and are retained in the cytoplasm and could no longer exert their anti-senescent and anti-stress roles, resulting in increased cellular senescence. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Circular RNAs are a subclass of non-coding RNAs detected within mammalian cells. This study was designed to test the roles of a circular RNA circ-Foxo3 in senescence using in vitro and in vivo approaches. METHODS AND RESULTS: Using the approaches of molecular and cellular biology, we show that a circular RNA generated from a member of the forkhead family of transcription factors, Foxo3, namely circ-Foxo3, was highly expressed in heart samples of aged patients and mice, which was correlated with markers of cellular senescence. Doxorubicin-induced cardiomyopathy was aggravated by ectopic expression of circ-Foxo3 but was relieved by silencing endogenous circ-Foxo3. We also found that silencing circ-Foxo3 inhibited senescence of mouse embryonic fibroblasts and that ectopic expression of circ-Foxo3 induced senescence. We found that circ-Foxo3 was mainly distributed in the cytoplasm, where it interacted with the anti-senescent protein ID-1 and the transcription factor E2F1, as well as the anti-stress proteins FAK and HIF1α. CONCLUSION: We conclude that ID-1, E2F1, FAK, and HIF1α interact with circ-Foxo3 and are retained in the cytoplasm and could no longer exert their anti-senescent and anti-stress roles, resulting in increased cellular senescence. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Ju Zhang; Xiuli Zhang; Cuidan Li; Liya Yue; Nan Ding; Tim Riordan; Li Yang; Yang Li; Charles Jen; Sen Lin; Dongsheng Zhou; Fei Chen Journal: RNA Biol Date: 2019-01-18 Impact factor: 4.652