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

ABSTRACT: 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 ROR? directly regulates Npas2 expression in vivo. Although the rhythmicity of Npas2 mRNA expression was maintained in ROR?(-/-) mice, the peak level of expression was significantly reduced in several tissues, while loss of ROR? had little effect. Inversely, overexpression of ROR? in hepatoma Hepa1-6 cells greatly induced the expression of Npas2. ROR?-activated Npas2 transcription directly by binding two ROREs in its proximal promoter. ChIP analysis demonstrated that ROR? was recruited to this promoter in the liver of wild-type mice, but not ROR?-deficient mice. Activation of Npas2 correlated positively with chromatin accessibility and level of H3K9 acetylation. The activation of Npas2 by ROR? was repressed by co-expression with Rev-Erb? 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 ROR?. Our results indicate that ROR? and Rev-Erb? 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.

SUBMITTER: Takeda Y

PROVIDER: S-EPMC3113563 | biostudies-other | 2011 Jun

REPOSITORIES: biostudies-other

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

Takeda Yukimasa Y Kang Hong Soon HS Angers Martin M Jetten Anton M AM

Nucleic acids research 20110211 11

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 ...[more]

PMID: 21317191

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Project description:In mammals, circadian rhythms are essential for coordinating the timing of various metabolic processes. The Clock gene regulates diurnal plasma triglyceride fluctuation through nuclear receptor small heterodimer partner (Shp; Nr0b2). Given that SHP is a critical regulator of metabolism in the liver, it is unknown whether SHP is necessary to coordinate metabolism and circadian rhythms. Shp(+/+) and Shp(-/-) mice on a C57BL/6 background (n = 3-5/group) were fed a standard chow diet and water ad libitum. Serum and livers were collected at zeitgeber time 2, 6, 10, 14, 18, and 22. In vivo and in vitro assays included RNA sequencing, quantitative polymerase chain reaction, very-low-density lipoprotein production, adenovirus overexpression and small interfering RNA knockdown, serum parameters, circadian locomotor activity, Oil Red O staining, transient transfection, luciferase reporter assay, chromatin immunoprecipitation assay, gel-shift assay, coimmunoprecipitation, and western blottings. Shp deficiency had a robust global impact on major liver metabolic genes. Several components of the liver clock, including peroxisome proliferator-activated receptor-?, coactivator 1 (Pgc-1?), neuronal PAS domain-containing protein 2 (Npas2), and retinoic acid-related orphan receptor (Ror)?/? were sharply induced in Shp(-/-) liver. At the molecular level, SHP inhibited Npas2 gene transcription and promoter activity through interaction with Ror? to repress Ror? transactivation and by interacting with Rev-erb? to enhance its inhibition of Ror? activity. Conversely, Npas2 controlled the circadian rhythm of Shp expression by binding rhythmically to the Shp promoter, which was enhanced by nicotinamide adenine dinucleotide, but not nicotinamide adenine dinucleotide phosphate. Phenotypically, Npas2 deficiency induced severe steatosis in Shp(-/-) mice, which was attributed to the dysregulation of lipoprotein metabolism.Shp and Npas2 crosstalk is essential to maintain hepatic lipid homeostasis.

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

Publications

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

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