Clock‐dependent and independent transcriptional control of the two isoforms from the mouse <i>Rorγ</i>gene

Mongrain, Valérie; Ruan, Xuan; Dardente, Hugues; Fortier, Erin E.; Cermakian, Nicolas

doi:10.1111/j.1365-2443.2008.01237.x

Cited by 32 publications

(28 citation statements)

References 54 publications

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“…Figure 1J shows that particularly RORγ1 , the only RORγ isoform expressed in liver, showed a robust oscillatory pattern of expression, while RORα1 , which is expressed at low levels, has a moderate and RORα4 , which in liver is the predominant α isoform, exhibited a weak oscillatory pattern consistent with earlier observations (16,20,52). Loss of RORγ or RORα expression had little effect on the circadian expression of RORα1 or α4 and RORγ1 mRNA, respectively, suggesting that RORα and RORγ are regulated independently from each other (Figure 1J).…”

Section: Resultssupporting

confidence: 88%

Retinoic acid-related orphan receptor γ directly regulates neuronal PAS domain protein 2 transcription in vivo

Takeda

Kang

Angers

et al. 2011

Nucleic Acids Research

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Retinoic acid-related orphan receptors (RORs) and the basic helix–loop–helix-PAS transcription factor Npas2 have been implicated in the control of circadian rhythm. In this study, we demonstrate that RORγ directly regulates Npas2 expression in vivo. Although the rhythmicity of Npas2 mRNA expression was maintained in RORγ−/− mice, the peak level of expression was significantly reduced in several tissues, while loss of RORα had little effect. Inversely, overexpression of RORγ in hepatoma Hepa1-6 cells greatly induced the expression of Npas2. RORγ-activated Npas2 transcription directly by binding two ROREs in its proximal promoter. ChIP analysis demonstrated that RORγ was recruited to this promoter in the liver of wild-type mice, but not RORγ-deficient mice. Activation of Npas2 correlated positively with chromatin accessibility and level of H3K9 acetylation. The activation of Npas2 by RORγ was repressed by co-expression with Rev-Erbα or addition of the ROR inverse agonist T0901317. Npas2 expression was also significantly enhanced during brown adipose differentiation and that this induction was greatly suppressed in adipose cells lacking RORγ. Our results indicate that RORγ and Rev-Erbα are part of a feed-back loop that regulates the circadian expression of Npas2 suggesting a regulatory role for these receptors in Npas2-dependent physiological processes.

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Section: Resultssupporting

confidence: 88%

Retinoic acid-related orphan receptor γ directly regulates neuronal PAS domain protein 2 transcription in vivo

Takeda

Kang

Angers

et al. 2011

Nucleic Acids Research

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“…Since Rorγt is not under circadian control but could be regulated by transcription factors that bind E-boxes it could explain the up regulation of Bmal1 . Furthermore, up-regulation of StAR could also be explained by the down-regulation of Per1 [69]. Per1 has previously been shown to be down regulated in Crem −/− mice [68] also confirming our results.…”

Section: Discussionsupporting

confidence: 91%

Novel Insights into the Downstream Pathways and Targets Controlled by Transcription Factors CREM in the Testis

et al. 2012

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The essential role of the Crem gene in normal sperm development is widely accepted and is confirmed by azoospermia in male mice lacking the Crem gene. The exact number of genes affected by Crem absence is not known, however a large difference has been observed recently between the estimated number of differentially expressed genes found in Crem knock-out (KO) mice compared to the number of gene loci bound by CREM. We therefore re-examined global gene expression in male mice lacking the Crem gene using whole genome transcriptome analysis with Affymetrix microarrays and compared the lists of differentially expressed genes from Crem−/− mice to a dataset of genes where binding of CREM was determined by Chip-seq. We determined the global effect of CREM on spermatogenesis as well as distinguished between primary and secondary effects of the CREM absence. We demonstrated that the absence of Crem deregulates over 4700 genes in KO testis. Among them are 101 genes associated with spermatogenesis 41 of which are bound by CREM and are deregulated in Crem KO testis. Absence of several of these genes in mouse models has proven their importance for normal spermatogenesis and male fertility. Our study showed that the absence of Crem plays a more important role on different aspects of spermatogenesis as estimated previously, with its impact ranging from apoptosis induction to deregulation of major circadian clock genes, steroidogenesis and the cell-cell junction dynamics. Several new genes important for normal spermatogenesis and fertility are down-regulated in KO testis and are therefore possible novel targets of CREM.

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“…ChIP-Seq analysis showing an association of RORγ with the regulatory region of several of these genes, including Insig2a and Elovl3 , suggested that these genes are regulated directly by RORγ. Studies showing that the diurnal expression of RORγ is directly regulated by the circadian clock machinery (15,16,18), together with our findings that the phase of the diurnal pattern of expression of several of these genes closely follows that of RORγ, suggest a connection between the diurnal regulation of these metabolic genes, the rhythmic expression of RORγ, and the circadian clock. These observations are further consistent with our hypothesis that RORγ functions as a transcriptional mediator that regulates the rhythmic expression of certain metabolic genes downstream of the clock machinery (Figure 7C).…”

Section: Discussionsupporting

confidence: 72%

Retinoid acid-related orphan receptor γ, RORγ, participates in diurnal transcriptional regulation of lipid metabolic genes

Takeda

Kang

Lih

et al. 2014

Nucleic Acids Research

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The hepatic circadian clock plays a pivotal role in regulating major aspects of energy homeostasis and lipid metabolism. In this study, we show that RORγ robustly regulates the rhythmic expression of several lipid metabolic genes, including the insulin-induced gene 2a, Insig2a, elongation of very long chain fatty acids-like 3, Elovl3 and sterol 12α-hydroxylase, Cyp8b1, by enhancing their expression at ZT20-4. The time-dependent increase in their expression correlates with the rhythmic expression pattern of RORγ. The enhanced recruitment of RORγ to ROREs in their promoter region, increased histone acetylation, and reporter and mutation analysis support the concept that RORγ regulates the transcription of several lipid metabolic genes directly by binding ROREs in their promoter regulatory region. Consistent with the disrupted expression of a number of lipid metabolic genes, loss of RORγ reduced the level of several lipids in liver and blood in a ZT-preferred manner. Particularly the whole-body bile acid pool size was considerably reduced in RORγ−/− mice in part through its regulation of several Cyp genes. Similar observations were made in liver-specific RORγ-deficient mice. Altogether, our study indicates that RORγ functions as an important link between the circadian clock and the transcriptional regulation of several metabolic genes.

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Clock‐dependent and independent transcriptional control of the two isoforms from the mouse Rorγgene

Cited by 32 publications

References 54 publications

Retinoic acid-related orphan receptor γ directly regulates neuronal PAS domain protein 2 transcription in vivo

Retinoic acid-related orphan receptor γ directly regulates neuronal PAS domain protein 2 transcription in vivo

Novel Insights into the Downstream Pathways and Targets Controlled by Transcription Factors CREM in the Testis

Retinoid acid-related orphan receptor γ, RORγ, participates in diurnal transcriptional regulation of lipid metabolic genes

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