Combinatorial Regulation Of Hepatic Cytoplasmic Signaling And Nuclear Transcriptional Events By The Ogt/Rev-Erb Alpha Complex

The nuclear receptor REV-ERB alpha 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-ERB alpha-interacting protein. By shielding cytoplasmic OGT from proteasomal degradation and favoring OGT activity in the nucleus, REV-ERB alpha cyclically increased O-GlcNAcylation of multiple cytoplasmic and nuclear proteins as a function of its rhythmically regulated expression, while REV-ERB alpha ligands mostly affected cytoplasmic OGT activity. We illustrate this finding by showing that REV-ERB alpha 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-ERB alpha expression. REV-ERB alpha enhanced TET activity and DNA hydroxymethylated cytosine (5hmC) levels in the vicinity of REV-ERB alpha genomic binding sites. As an example, we show that the REV-ERB alpha/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-ERB alpha 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.