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

Alexandre Berthier; Manjula Vinod; Geoffrey Porez; Agata Steenackers; Jérémy Alexandre; Nao Yamakawa; Céline Gheeraert; Maheul Ploton; Xavier Marechal; Julie Dubois-Chevalier; Agnès Hovasse; Christine Schaeffer-Reiss; Sarah Cianférani; Christian Rolando; Fabrice Bray; Hélène Duez; Jérôme Eeckhoute; Tony Lefebvre; Bart Staels; Philippe Lefebvre

doi:10.1073/pnas.1805397115

Journal articles

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 RNMCD - Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011

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 MSAP - Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - USR 3290

6 FRABio - Biochimie Structurale et Fonctionnelle des Assemblages Biomoléculaires - CNRS FR3688

7 IMEC - Institut Michel Eugène Chevreul - FR 2638

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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Journal articles

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Life Sciences [q-bio] / Biochemistry, Molecular Biology

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

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

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