| First Author | Berthier A | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 47 | Pages | E11033-E11042 |
| PubMed ID | 30397120 | Mgi Jnum | J:267259 |
| Mgi Id | MGI:6258482 | Doi | 10.1073/pnas.1805397115 |
| Citation | Berthier A, et al. (2018) Combinatorial regulation of hepatic cytoplasmic signaling and nuclear transcriptional events by the OGT/REV-ERBalpha complex. Proc Natl Acad Sci U S A 115(47):E11033-E11042 |
| abstractText | The nuclear receptor REV-ERBalpha integrates the circadian clock with hepatic glucose and lipid metabolism by nucleating transcriptional comodulators at genomic regulatory regions. An interactomic approach identified O-GlcNAc transferase (OGT) as a REV-ERBalpha-interacting protein. By shielding cytoplasmic OGT from proteasomal degradation and favoring OGT activity in the nucleus, REV-ERBalpha cyclically increased O-GlcNAcylation of multiple cytoplasmic and nuclear proteins as a function of its rhythmically regulated expression, while REV-ERBalpha ligands mostly affected cytoplasmic OGT activity. We illustrate this finding by showing that REV-ERBalpha controls OGT-dependent activities of the cytoplasmic protein kinase AKT, an essential relay in insulin signaling, and of ten-of-eleven translocation (TET) enzymes in the nucleus. AKT phosphorylation was inversely correlated to REV-ERBalpha expression. REV-ERBalpha enhanced TET activity and DNA hydroxymethylated cytosine (5hmC) levels in the vicinity of REV-ERBalpha genomic binding sites. As an example, we show that the REV-ERBalpha/OGT complex modulates SREBP-1c gene expression throughout the fasting/feeding periods by first repressing AKT phosphorylation and by epigenomically priming the Srebf1 promoter for a further rapid response to insulin. Conclusion: REV-ERBalpha regulates cytoplasmic and nuclear OGT-controlled processes that integrate at the hepatic SREBF1 locus to control basal and insulin-induced expression of the temporally and nutritionally regulated lipogenic SREBP-1c transcript. |
