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Transcriptional regulation of N6-methyladenosine orchestrates sex-dimorphic metabolic traits.
Salisbury, David A; Casero, David; Zhang, Zhengyi; Wang, Dan; Kim, Jason; Wu, Xiaohui; Vergnes, Laurent; Mirza, Aashiq H; Leon-Mimila, Paola; Williams, Kevin J; Huertas-Vazquez, Adriana; Jaffrey, Samie R; Reue, Karen; Chen, Jianjun; Sallam, Tamer.
Afiliação
  • Salisbury DA; Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Casero D; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
  • Zhang Z; Molecular Biology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA.
  • Wang D; F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Kim J; Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Wu X; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
  • Vergnes L; Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Mirza AH; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
  • Leon-Mimila P; Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Williams KJ; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
  • Huertas-Vazquez A; Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Jaffrey SR; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
  • Reue K; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
  • Chen J; Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY, USA.
  • Sallam T; Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Nat Metab ; 3(7): 940-953, 2021 07.
Article em En | MEDLINE | ID: mdl-34282353
ABSTRACT
Males and females exhibit striking differences in the prevalence of metabolic traits including hepatic steatosis, a key driver of cardiometabolic morbidity and mortality. RNA methylation is a widespread regulatory mechanism of transcript turnover. Here, we show that presence of the RNA modification N6-methyladenosine (m6A) triages lipogenic transcripts for degradation and guards against hepatic triglyceride accumulation. In male but not female mice, this protective checkpoint stalls under lipid-rich conditions. Loss of m6A control in male livers increases hepatic triglyceride stores, leading to a more 'feminized' hepatic lipid composition. Crucially, liver-specific deletion of the m6A complex protein Mettl14 from male and female mice significantly diminishes sex-specific differences in steatosis. We further surmise that the m6A installing machinery is subject to transcriptional control by the sex-responsive BCL6-STAT5 axis in response to dietary conditions. These data show that m6A is essential for precise and synchronized control of lipogenic enzyme activity and provide insights into the molecular basis for the existence of sex-specific differences in hepatic lipid traits.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transcrição Gênica / Adenosina / Regulação da Expressão Gênica / Característica Quantitativa Herdável / Metabolismo Energético Idioma: En Ano de publicação: 2021 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transcrição Gênica / Adenosina / Regulação da Expressão Gênica / Característica Quantitativa Herdável / Metabolismo Energético Idioma: En Ano de publicação: 2021 Tipo de documento: Article