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Journal articles
Combinatorial regulation of hepatic cytoplasmic signaling and nuclear transcriptional events by the OGT/REV-ERBα complex
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.
Cited literature [49 references]
https://www.hal.inserm.fr/inserm-01924835
Contributor : Marie-Hélène Derudas <>
Submitted on : Friday, November 16, 2018 - 12:11:05 PM
Last modification on : Wednesday, October 21, 2020 - 3:41:53 AM
Long-term archiving on: : Sunday, February 17, 2019 - 1:50:17 PM
Contributor : Marie-Hélène Derudas <>
Submitted on : Friday, November 16, 2018 - 12:11:05 PM
Last modification on : Wednesday, October 21, 2020 - 3:41:53 AM
Long-term archiving on: : Sunday, February 17, 2019 - 1:50:17 PM
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1805397115.full.pdf
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