| Literature DB >> 30428350 |
Xiang Zhong1, Jiayao Yu2, Katya Frazier3, Xiaocheng Weng4, Yi Li2, Candace M Cham3, Kyle Dolan3, Xiaorong Zhu3, Nathaniel Hubert3, Yun Tao3, Fanfei Lin3, Kristina Martinez-Guryn3, Yong Huang3, Tian Wang2, Jianzhao Liu4, Chuan He4, Eugene B Chang5, Vanessa Leone6.
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.Entities:
Keywords: Bmal1; METTL3; PPaRα; ROS; YTHDF2; circadian clock; hepatic; lipid metabolism; m(6)A RNA methylation; post-transcriptional regulation
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Year: 2018 PMID： 30428350 PMCID： PMC6532766 DOI： 10.1016/j.celrep.2018.10.068
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423