2. Academic Validation
  3. Circadian Clock Regulation of Hepatic Lipid Metabolism by Modulation of m6A mRNA Methylation

Circadian Clock Regulation of Hepatic Lipid Metabolism by Modulation of m6A mRNA Methylation

  • Cell Rep. 2018 Nov 13;25(7):1816-1828.e4. doi: 10.1016/j.celrep.2018.10.068.
Xiang Zhong 1,  Jiayao Yu 2,  Katya Frazier 3,  Xiaocheng Weng 4,  Yi Li 2,  Candace M Cham 3,  Kyle Dolan 3,  Xiaorong Zhu 3,  Nathaniel Hubert 3,  Yun Tao 3,  Fanfei Lin 3,  Kristina Martinez-Guryn 3,  Yong Huang 3,  Tian Wang 2,  Jianzhao Liu 4,  Chuan He 4,  Eugene B Chang 5,  Vanessa Leone 6
Affiliations

Affiliations

  • 1 College of Animal Science and Technology, Nanjing Agricultural University, Jiangsu, Nanjing 210095, PR China; Department of Medicine, University of Chicago, Chicago, IL 60637, USA. Electronic address: [email protected].
  • 2 College of Animal Science and Technology, Nanjing Agricultural University, Jiangsu, Nanjing 210095, PR China.
  • 3 Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
  • 4 Department of Chemistry, University of Chicago, Chicago, IL 60637, USA; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
  • 5 Department of Medicine, University of Chicago, Chicago, IL 60637, USA. Electronic address: [email protected].
  • 6 Department of Medicine, University of Chicago, Chicago, IL 60637, USA. Electronic address: [email protected].
PMID: 30428350 DOI: 10.1016/j.celrep.2018.10.068
Abstract

Transcriptional regulation of circadian rhythms is essential for lipid metabolic homeostasis, disruptions of which can lead to metabolic diseases. Whether N6-methyladenosine (m6A) mRNA methylation impacts circadian regulation of lipid metabolism is unclear. Here, we show m6A mRNA methylation oscillations in murine liver depend upon a functional circadian clock. Hepatic deletion of Bmal1 increases m6A mRNA methylation, particularly of PPARα. Inhibition of m6A methylation via knockdown of m6A methyltransferase METTL3 decreases PPARα m6A abundance and increases PPARα mRNA lifetime and expression, reducing lipid accumulation in cells in vitro. Mechanistically, YTHDF2 binds to PPARα to mediate its mRNA stability to regulate lipid metabolism. Induction of Reactive Oxygen Species both in vitro and in vivo increases PPARα transcript m6A levels, revealing a possible mechanism for circadian disruption on m6A mRNA methylation. These data show that m6A RNA methylation is important for circadian regulation of downstream genes and lipid metabolism, impacting metabolic outcomes.

Keywords

Bmal1; METTL3; PPaRα; ROS; YTHDF2; circadian clock; hepatic; lipid metabolism; m(6)A RNA methylation; post-transcriptional regulation.

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