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Btg2 is a Negative Regulator of Cardiomyocyte Hypertrophy through a Decrease in Cytosolic RNA

Under hypertrophic stimulation, cardiomyocytes enter a hypermetabolic state and accelerate biomass accumulation. Although the molecular pathways that regulate protein levels are well-studied, the functional implications of RNA accumulation and its regulatory mechanisms in cardiomyocytes remain elusi...

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Autores principales: Masumura, Yuki, Higo, Shuichiro, Asano, Yoshihiro, Kato, Hisakazu, Yan, Yi, Ishino, Saki, Tsukamoto, Osamu, Kioka, Hidetaka, Hayashi, Takaharu, Shintani, Yasunori, Yamazaki, Satoru, Minamino, Tetsuo, Kitakaze, Masafumi, Komuro, Issei, Takashima, Seiji, Sakata, Yasushi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4921833/
https://www.ncbi.nlm.nih.gov/pubmed/27346836
http://dx.doi.org/10.1038/srep28592
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author Masumura, Yuki
Higo, Shuichiro
Asano, Yoshihiro
Kato, Hisakazu
Yan, Yi
Ishino, Saki
Tsukamoto, Osamu
Kioka, Hidetaka
Hayashi, Takaharu
Shintani, Yasunori
Yamazaki, Satoru
Minamino, Tetsuo
Kitakaze, Masafumi
Komuro, Issei
Takashima, Seiji
Sakata, Yasushi
author_facet Masumura, Yuki
Higo, Shuichiro
Asano, Yoshihiro
Kato, Hisakazu
Yan, Yi
Ishino, Saki
Tsukamoto, Osamu
Kioka, Hidetaka
Hayashi, Takaharu
Shintani, Yasunori
Yamazaki, Satoru
Minamino, Tetsuo
Kitakaze, Masafumi
Komuro, Issei
Takashima, Seiji
Sakata, Yasushi
author_sort Masumura, Yuki
collection PubMed
description Under hypertrophic stimulation, cardiomyocytes enter a hypermetabolic state and accelerate biomass accumulation. Although the molecular pathways that regulate protein levels are well-studied, the functional implications of RNA accumulation and its regulatory mechanisms in cardiomyocytes remain elusive. Here, we have elucidated the quantitative kinetics of RNA in cardiomyocytes through single cell imaging and c-Myc (Myc)-mediated hypermetabolic analytical model using cultured cardiomyocytes. Nascent RNA labeling combined with single cell imaging demonstrated that Myc protein significantly increased the amount of global RNA production per cardiomyocyte. Chromatin immunoprecipitation with high-throughput sequencing clarified that overexpressed Myc bound to a specific set of genes and recruits RNA polymerase II. Among these genes, we identified Btg2 as a novel target of Myc. Btg2 overexpression significantly reduced cardiomyocyte surface area. Conversely, shRNA-mediated knockdown of Btg2 accelerated adrenergic stimulus-induced hypertrophy. Using mass spectrometry analysis, we determined that Btg2 binds a series of proteins that comprise mRNA deadenylation complexes. Intriguingly, Btg2 specifically suppresses cytosolic, but not nuclear, RNA levels. Btg2 knockdown further enhances cytosolic RNA accumulation in cardiomyocytes under adrenergic stimulation, suggesting that Btg2 negatively regulates reactive hypertrophy by negatively regulating RNA accumulation. Our findings provide insight into the functional significance of the mechanisms regulating RNA levels in cardiomyocytes.
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spelling pubmed-49218332016-06-28 Btg2 is a Negative Regulator of Cardiomyocyte Hypertrophy through a Decrease in Cytosolic RNA Masumura, Yuki Higo, Shuichiro Asano, Yoshihiro Kato, Hisakazu Yan, Yi Ishino, Saki Tsukamoto, Osamu Kioka, Hidetaka Hayashi, Takaharu Shintani, Yasunori Yamazaki, Satoru Minamino, Tetsuo Kitakaze, Masafumi Komuro, Issei Takashima, Seiji Sakata, Yasushi Sci Rep Article Under hypertrophic stimulation, cardiomyocytes enter a hypermetabolic state and accelerate biomass accumulation. Although the molecular pathways that regulate protein levels are well-studied, the functional implications of RNA accumulation and its regulatory mechanisms in cardiomyocytes remain elusive. Here, we have elucidated the quantitative kinetics of RNA in cardiomyocytes through single cell imaging and c-Myc (Myc)-mediated hypermetabolic analytical model using cultured cardiomyocytes. Nascent RNA labeling combined with single cell imaging demonstrated that Myc protein significantly increased the amount of global RNA production per cardiomyocyte. Chromatin immunoprecipitation with high-throughput sequencing clarified that overexpressed Myc bound to a specific set of genes and recruits RNA polymerase II. Among these genes, we identified Btg2 as a novel target of Myc. Btg2 overexpression significantly reduced cardiomyocyte surface area. Conversely, shRNA-mediated knockdown of Btg2 accelerated adrenergic stimulus-induced hypertrophy. Using mass spectrometry analysis, we determined that Btg2 binds a series of proteins that comprise mRNA deadenylation complexes. Intriguingly, Btg2 specifically suppresses cytosolic, but not nuclear, RNA levels. Btg2 knockdown further enhances cytosolic RNA accumulation in cardiomyocytes under adrenergic stimulation, suggesting that Btg2 negatively regulates reactive hypertrophy by negatively regulating RNA accumulation. Our findings provide insight into the functional significance of the mechanisms regulating RNA levels in cardiomyocytes. Nature Publishing Group 2016-06-27 /pmc/articles/PMC4921833/ /pubmed/27346836 http://dx.doi.org/10.1038/srep28592 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Masumura, Yuki
Higo, Shuichiro
Asano, Yoshihiro
Kato, Hisakazu
Yan, Yi
Ishino, Saki
Tsukamoto, Osamu
Kioka, Hidetaka
Hayashi, Takaharu
Shintani, Yasunori
Yamazaki, Satoru
Minamino, Tetsuo
Kitakaze, Masafumi
Komuro, Issei
Takashima, Seiji
Sakata, Yasushi
Btg2 is a Negative Regulator of Cardiomyocyte Hypertrophy through a Decrease in Cytosolic RNA
title Btg2 is a Negative Regulator of Cardiomyocyte Hypertrophy through a Decrease in Cytosolic RNA
title_full Btg2 is a Negative Regulator of Cardiomyocyte Hypertrophy through a Decrease in Cytosolic RNA
title_fullStr Btg2 is a Negative Regulator of Cardiomyocyte Hypertrophy through a Decrease in Cytosolic RNA
title_full_unstemmed Btg2 is a Negative Regulator of Cardiomyocyte Hypertrophy through a Decrease in Cytosolic RNA
title_short Btg2 is a Negative Regulator of Cardiomyocyte Hypertrophy through a Decrease in Cytosolic RNA
title_sort btg2 is a negative regulator of cardiomyocyte hypertrophy through a decrease in cytosolic rna
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4921833/
https://www.ncbi.nlm.nih.gov/pubmed/27346836
http://dx.doi.org/10.1038/srep28592
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