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NFAT5-mediated CACNA1C expression is critical for cardiac electrophysiological development and maturation.
Li, Wei; Zheng, Nai-Zhong; Yuan, Qi; Xu, Ke; Yang, Fan; Gu, Lei; Zheng, Gu-Yan; Luo, Guo-Jie; Fan, Chun; Ji, Guang-Ju; Zhang, Bo; Cao, Huiqing; Tian, Xiao-Li.
Afiliación
  • Li W; Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, 5 Yiheyuan Road, Beijing, 100871, China.
  • Zheng NZ; Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, 5 Yiheyuan Road, Beijing, 100871, China.
  • Yuan Q; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing, 100101, China.
  • Xu K; Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, 5 Yiheyuan Road, Beijing, 100871, China.
  • Yang F; Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, 5 Yiheyuan Road, Beijing, 100871, China.
  • Gu L; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing, 100101, China.
  • Zheng GY; Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, 5 Yiheyuan Road, Beijing, 100871, China.
  • Luo GJ; School of Electronics Engineering and Computer Science, Peking University, 5 Yiheyuan Road, Beijing, 100871, China.
  • Fan C; Department of Biomedical Engineering, Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
  • Ji GJ; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing, 100101, China.
  • Zhang B; Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, 5 Yiheyuan Road, Beijing, 100871, China.
  • Cao H; Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, 5 Yiheyuan Road, Beijing, 100871, China. caohuiqing@pku.edu.cn.
  • Tian XL; Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, 5 Yiheyuan Road, Beijing, 100871, China. tianxiaoli@pku.edu.cn.
J Mol Med (Berl) ; 94(9): 993-1002, 2016 09.
Article en En | MEDLINE | ID: mdl-27368804
UNLABELLED: Entry of calcium into cardiomyocyte via L-type calcium channel (LTCC) is fundamental to cardiac contraction. CACNA1C, a type of LTCC and a hallmark of a matured ventricular myocyte, is developmentally regulated. Here, we identified 138 potential transcription factors by a comparative genomic study on 5-kb promoter regions of CACNA1C gene across eight vertebrate species, and showed that six factors were developmentally regulated with the expression of Cacna1c in mouse P19cl6 in vitro cardiomyocyte differentiation model. We further demonstrated that the nuclear factor of activated T cells 5 (Nfat5) bound to a consensus sequence TGGAAGCGTTC and activated the transcription of Cacna1c. The siRNA-mediated knockdown of Nfat5 suppressed the expression of Cacna1c and decreased L-type calcium current in mouse neonatal cardiomyocytes. Furthermore, morpholino-mediated knockdown of nfat5 in zebrafish prohibited the expression of cacna1c and resulted in a non-contractile ventricle, while over-expression of either cacna1c or nfat5 rescued this impaired phenotype. Thus, NFAT5-mediated expression of CACNA1C is evolutionarily conserved and critical for cardiac electrophysiological development and maturation of cardiomyocyte. KEY MESSAGE: Nfat5 binds to a consensus sequence TGGAAGCGTTC in the promoter of Cacna1c. Nfat5 activates the transcription of Cacna1c. Nfat5 knockdown suppresses Cacna1c expression, decreases L-type calcium current, and results in non-beating ventricle. NFAT5-mediated expression of CACNA1C is evolutionarily conserved. NFAT5-mediated CACNA1C expression is critical for cardiac electrophysiological development and maturation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Diferenciación Celular / Regulación de la Expresión Génica / Canales de Calcio Tipo L / Miocitos Cardíacos / Fenómenos Electrofisiológicos Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Mol Med (Berl) Asunto de la revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Año: 2016 Tipo del documento: Article País de afiliación: China Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Diferenciación Celular / Regulación de la Expresión Génica / Canales de Calcio Tipo L / Miocitos Cardíacos / Fenómenos Electrofisiológicos Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Mol Med (Berl) Asunto de la revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Año: 2016 Tipo del documento: Article País de afiliación: China Pais de publicación: Alemania