Combinatorial regulation of hepatic cytoplasmic signaling and nuclear transcriptional events by the OGT/REV-ERBα complex.
Alexandre BerthierManjula VinodGeoffrey PorezAgata SteenackersJérémy AlexandreNao YamakawaCéline GheeraertMaheul PlotonXavier MaréchalJulie Dubois-ChevalierAgnès HovasseChristine Schaeffer-ReissSarah CianféraniChristian RolandoFabrice BrayHélène DuezJérôme EeckhouteTony LefebvreBart StaelsPhilippe LefebvrePublished in: Proceedings of the National Academy of Sciences of the United States of America (2018)
The nuclear receptor REV-ERBα 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-ERBα-interacting protein. By shielding cytoplasmic OGT from proteasomal degradation and favoring OGT activity in the nucleus, REV-ERBα cyclically increased O-GlcNAcylation of multiple cytoplasmic and nuclear proteins as a function of its rhythmically regulated expression, while REV-ERBα ligands mostly affected cytoplasmic OGT activity. We illustrate this finding by showing that REV-ERBα 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-ERBα expression. REV-ERBα enhanced TET activity and DNA hydroxymethylated cytosine (5hmC) levels in the vicinity of REV-ERBα genomic binding sites. As an example, we show that the REV-ERBα/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-ERBα 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.
Keyphrases
- gene expression
- transcription factor
- type diabetes
- poor prognosis
- protein kinase
- cell proliferation
- signaling pathway
- binding protein
- dna methylation
- copy number
- glycemic control
- oxidative stress
- adipose tissue
- blood glucose
- skeletal muscle
- high glucose
- quantum dots
- diabetic rats
- heat shock protein
- protein protein
- heat shock