Combinatorial regulation of hepatic cytoplasmic signaling and nuclear transcriptional events by the OGT/REV-ERBα complex

Alexandre Berthier 1 Manjula Vinod 1 Geoffrey Porez 1 Agata Steenackers 2 Jérémy Alexandre 1 Nao Yamakawa 2 Céline Gheeraert 1 Maheul Ploton 1 Xavier Marechal 1 Julie Dubois-Chevalier 1 Agnès Hovasse 3, 4 Christine Schaeffer-Reiss 3, 4 Sarah Cianférani 4, 3 Christian Rolando 5, 6, 7 Fabrice Bray 5, 6, 7 Hélène Duez 1 Jérôme Eeckhoute 1 Tony Lefebvre 2 Bart Staels 1 Philippe Lefebvre 1, *
* Corresponding author
1 EGID - Récepteurs nucléaires, maladies cardiovasculaires et diabète
2 UGSF - Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576
3 Laboratoire de Spectrométrie de Masse BioOrgan [Université de Strasbourg]
4 IPHC - Institut Pluridisciplinaire Hubert Curien
5 USR CNRS 3290 - Miniaturisation pour l'Analyse, la Synthèse & la Protéomique
6 FRABio - CNRS FR3688 - Fédération de Recherche Biochimie Structurale et Fonctionnelle des Assemblages Biomoléculaires
7 CNRS FR 2638 - Institut Michel Eugène Chevreul [Villeneuve d’Ascq]
Abstract : 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.
Keywords : metabolism signal transduction epigenomics O-GlcNAcylation REV-ERBα
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Alexandre Berthier, Manjula Vinod, Geoffrey Porez, Agata Steenackers, Jérémy Alexandre, et al.. Combinatorial regulation of hepatic cytoplasmic signaling and nuclear transcriptional events by the OGT/REV-ERBα complex. Proceedings of the National Academy of Sciences of the United States of America , National Academy of Sciences, 2018, Epub ahead of print. ⟨10.1073/pnas.1805397115⟩. ⟨inserm-01924835⟩

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