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.
journal_name
Cell Repjournal_title
Cell reportsauthors
Zhong X,Yu J,Frazier K,Weng X,Li Y,Cham CM,Dolan K,Zhu X,Hubert N,Tao Y,Lin F,Martinez-Guryn K,Huang Y,Wang T,Liu J,He C,Chang EB,Leone Vdoi
10.1016/j.celrep.2018.10.068subject
Has Abstractpub_date
2018-11-13 00:00:00pages
1816-1828.e4issue
7issn
2211-1247pii
S2211-1247(18)31672-3journal_volume
25pub_type
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