| First Author | Zhong X | Year | 2018 |
| Journal | Cell Rep | Volume | 25 |
| Issue | 7 | Pages | 1816-1828.e4 |
| PubMed ID | 30428350 | Mgi Jnum | J:270819 |
| Mgi Id | MGI:6278760 | Doi | 10.1016/j.celrep.2018.10.068 |
| Citation | Zhong X, et al. (2018) Circadian Clock Regulation of Hepatic Lipid Metabolism by Modulation of m(6)A mRNA Methylation. Cell Rep 25(7):1816-1828.e4 |
| abstractText | Transcriptional regulation of circadian rhythms is essential for lipid metabolic homeostasis, disruptions of which can lead to metabolic diseases. Whether N(6)-methyladenosine (m(6)A) mRNA methylation impacts circadian regulation of lipid metabolism is unclear. Here, we show m(6)A mRNA methylation oscillations in murine liver depend upon a functional circadian clock. Hepatic deletion of Bmal1 increases m(6)A mRNA methylation, particularly of PPaRalpha. Inhibition of m(6)A methylation via knockdown of m(6)A methyltransferase METTL3 decreases PPaRalpha m(6)A abundance and increases PPaRalpha mRNA lifetime and expression, reducing lipid accumulation in cells in vitro. Mechanistically, YTHDF2 binds to PPaRalpha to mediate its mRNA stability to regulate lipid metabolism. Induction of reactive oxygen species both in vitro and in vivo increases PPaRalpha transcript m(6)A levels, revealing a possible mechanism for circadian disruption on m(6)A mRNA methylation. These data show that m(6)A RNA methylation is important for circadian regulation of downstream genes and lipid metabolism, impacting metabolic outcomes. |
