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The orphan nuclear receptor TR4 regulates erythroid cell proliferation and maturation.

ABSTRACT: The orphan nuclear receptors TR4 (NR2C2) and TR2 (NR2C1) are the DNA-binding subunits of the macromolecular complex, direct repeat erythroid-definitive, which has been shown to repress ?- and ?-globin transcription during adult definitive erythropoiesis. Previous studies implied that TR2 and TR4 act largely in a redundant manner during erythroid differentiation; however, during the course of routine genetic studies, we observed multiple variably penetrant phenotypes in the Tr4 mutants, suggesting that indirect effects of the mutation might be masked by multiple modifying genes. To test this hypothesis, Tr4^+/- mutant mice were bred into a congenic C57BL/6 background and their phenotypes were reexamined. Surprisingly, we found that homozygous Tr4 null mutant mice expired early during embryogenesis, around embryonic day 7.0, and well before erythropoiesis commences. We further found that Tr4^+/- erythroid cells failed to fully differentiate and exhibited diminished proliferative capacity. Analysis of Tr4^+/- mutant erythroid cells revealed that reduced TR4 abundance resulted in decreased expression of genes required for heme biosynthesis and erythroid differentiation (Alad and Alas2), but led to significantly increased expression of the proliferation inhibitory factor, cyclin dependent kinase inhibitor (Cdkn1c) These studies support a vital role for TR4 in promoting erythroid maturation and proliferation, and demonstrate that TR4 and TR2 execute distinct, individual functions during embryogenesis and erythroid differentiation.

SUBMITTER: Lee MP

PROVIDER: S-EPMC5721283 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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The orphan nuclear receptor TR4 regulates erythroid cell proliferation and maturation.

Lee Mary P MP Tanabe Osamu O Shi Lihong L Jearawiriyapaisarn Natee N Lucas Daniel D Engel James Douglas JD

Blood 20171010 23

The orphan nuclear receptors TR4 (NR2C2) and TR2 (NR2C1) are the DNA-binding subunits of the macromolecular complex, direct repeat erythroid-definitive, which has been shown to repress ε- and γ-globin transcription during adult definitive erythropoiesis. Previous studies implied that TR2 and TR4 act largely in a redundant manner during erythroid differentiation; however, during the course of routine genetic studies, we observed multiple variably penetrant phenotypes in the Tr4</ ...[more]

PMID: 29018082

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Project description:ObjectiveThe nuclear receptor TAK1/TR4/NR2C2 is expressed in several tissues that are important in the control of energy homeostasis. In this study, we investigate whether TAK1 functions as a regulator of lipid and energy homeostasis and has a role in metabolic syndrome.Research design and methodsWe generated TAK1-deficient (TAK1⁻(/)⁻) mice to study the function of TAK1 in the development of metabolic syndrome in aged mice and mice fed a high-fat diet (HFD). (Immuno)histochemical, biochemical, and gene expression profile analyses were performed to determine the effect of the loss of TAK1 expression on lipid homeostasis in liver and adipose tissues. In addition, insulin sensitivity, energy expenditure, and adipose-associated inflammation were compared in wild-type (WT) and TAK1⁻(/)⁻ mice fed a HFD.ResultsTAK1-deficient (TAK1⁻(/)⁻) mice are resistant to the development of age- and HFD-induced metabolic syndrome. Histo- and biochemical analyses showed significantly lower hepatic triglyceride levels and reduced lipid accumulation in adipose tissue in TAK1⁻(/)⁻ mice compared with WT mice. Gene expression profiling analysis revealed that the expression of several genes encoding proteins involved in lipid uptake and triglyceride synthesis and storage, including Cidea, Cidec, Mogat1, and CD36, was greatly decreased in the liver and primary hepatocytes of TAK1⁻(/)⁻ mice. Restoration of TAK1 expression in TAK1⁻(/)⁻ hepatocytes induced expression of several lipogenic genes. Moreover, TAK1⁻(/)⁻ mice exhibited reduced infiltration of inflammatory cells and expression of inflammatory genes in white adipose tissue, and were resistant to the development of glucose intolerance and insulin resistance. TAK1⁻(/)⁻ mice consume more oxygen and produce more carbon dioxide than WT mice, suggesting increased energy expenditure.ConclusionsOur data reveal that TAK1 plays a critical role in the regulation of energy and lipid homeostasis, and promotes the development of metabolic syndrome. TAK1 may provide a new therapeutic target in the management of obesity, diabetes, and liver steatosis.

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The orphan nuclear receptor TR4 regulates erythroid cell proliferation and maturation.

Publications

The orphan nuclear receptor TR4 regulates erythroid cell proliferation and maturation.

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