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Research ArticleSpecial Section on Epigenetic Regulation of Drug Metabolizing Enzymes and Transporters

Role of Multiple MicroRNAs in the Sexually Dimorphic Expression of Cyp2b9 in Mouse Liver

Xiaofeng Xie, Lingling Miao, Jun Yao, Chenchen Feng, Chenggang Li, Man Gao, Mingxia Liu, Likun Gong, Yizheng Wang, Xinming Qi and Jin Ren
Drug Metabolism and Disposition October 2013, 41 (10) 1732-1737; DOI: https://doi.org/10.1124/dmd.113.052217
Xiaofeng Xie
Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, (X.X., L.M., J.Y., C.F., C.L., M.G., M.L., L.G., X.Q., J.R.), Laboratory of Neural Signal Transduction, Institute of Neuroscience, Chinese Academy of Sciences (Y.W.), Shanghai, China
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Lingling Miao
Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, (X.X., L.M., J.Y., C.F., C.L., M.G., M.L., L.G., X.Q., J.R.), Laboratory of Neural Signal Transduction, Institute of Neuroscience, Chinese Academy of Sciences (Y.W.), Shanghai, China
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Jun Yao
Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, (X.X., L.M., J.Y., C.F., C.L., M.G., M.L., L.G., X.Q., J.R.), Laboratory of Neural Signal Transduction, Institute of Neuroscience, Chinese Academy of Sciences (Y.W.), Shanghai, China
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Chenchen Feng
Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, (X.X., L.M., J.Y., C.F., C.L., M.G., M.L., L.G., X.Q., J.R.), Laboratory of Neural Signal Transduction, Institute of Neuroscience, Chinese Academy of Sciences (Y.W.), Shanghai, China
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Chenggang Li
Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, (X.X., L.M., J.Y., C.F., C.L., M.G., M.L., L.G., X.Q., J.R.), Laboratory of Neural Signal Transduction, Institute of Neuroscience, Chinese Academy of Sciences (Y.W.), Shanghai, China
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Man Gao
Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, (X.X., L.M., J.Y., C.F., C.L., M.G., M.L., L.G., X.Q., J.R.), Laboratory of Neural Signal Transduction, Institute of Neuroscience, Chinese Academy of Sciences (Y.W.), Shanghai, China
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Mingxia Liu
Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, (X.X., L.M., J.Y., C.F., C.L., M.G., M.L., L.G., X.Q., J.R.), Laboratory of Neural Signal Transduction, Institute of Neuroscience, Chinese Academy of Sciences (Y.W.), Shanghai, China
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Likun Gong
Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, (X.X., L.M., J.Y., C.F., C.L., M.G., M.L., L.G., X.Q., J.R.), Laboratory of Neural Signal Transduction, Institute of Neuroscience, Chinese Academy of Sciences (Y.W.), Shanghai, China
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Yizheng Wang
Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, (X.X., L.M., J.Y., C.F., C.L., M.G., M.L., L.G., X.Q., J.R.), Laboratory of Neural Signal Transduction, Institute of Neuroscience, Chinese Academy of Sciences (Y.W.), Shanghai, China
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Xinming Qi
Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, (X.X., L.M., J.Y., C.F., C.L., M.G., M.L., L.G., X.Q., J.R.), Laboratory of Neural Signal Transduction, Institute of Neuroscience, Chinese Academy of Sciences (Y.W.), Shanghai, China
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Jin Ren
Center for Drug Safety Evaluation and Research, Shanghai Institute of Materia Medica, (X.X., L.M., J.Y., C.F., C.L., M.G., M.L., L.G., X.Q., J.R.), Laboratory of Neural Signal Transduction, Institute of Neuroscience, Chinese Academy of Sciences (Y.W.), Shanghai, China
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Abstract

Mouse cytochrome P450 2b9 (Cyp2b9) is a testosterone 16α-hydroxylase enzyme showing female-specific expression in many inbred mouse strains, including C57BL/6J. Previous studies have recognized that some sex-dependently secreted endogenous modulating factors were involved in the sexually dimorphic expression of Cyp2b9 through transcriptional regulation. In this study, we found evidence that some microRNAs contributed to the sexually biased expression of Cyp2b9 via post-transcriptional regulation. Cyp2b9 was upregulated in livers of hepatocyte-specific Dicer1 knockout mice at 3 weeks. The age-dependent downregulation of Cyp2b9 in the livers of male mice was diminished when Dicer1 was specifically knocked out in hepatocytes. When these data were combined with bioinformatics analysis and microRNA profiles of male and female mice, we found that 18 microRNAs were associated with the sexually dimorphic expression of Cyp2b9, which showed higher expression levels in male C57BL/6J mice when compared with females. Luciferase assays revealed that approximate half of these microRNAs repressed luciferase activity in a reporter system containing the 3′-untranslated region (3′-UTR) of Cyp2b9, and also inhibited Cyp2b9 protein expression. MicroRNA seed region mutation or mutations in putative binding sites of the microRNAs in Cyp2b9 3′-UTR led to the loss of the suppression of luciferase activity. There was also a negative correlation between the levels of these microRNAs and Cyp2b9. Our results suggested that multiple microRNAs participated in the regulation of Cyp2b9 expression, and that the lower expression levels of these microRNAs potentially contributed to the female-specific expression of Cyp2b9 in the livers of C57BL/6J mice.

Footnotes

    • Received April 1, 2013.
    • Accepted May 22, 2013.
  • Xiaofeng Xie and Lingling Miao contributed equally to this work.

  • This work was supported by the National Science and Technology Major Project [Grants 2012ZX09302-003 and 2012ZX09301-001-006].

  • This work has been submitted as part of Xiaofeng Xie’s Master thesis: Xiaofeng X (2012) Role of Dicer and microRNAs in the Development of Hepatocellular Carcinoma. M.Sc. thesis, Chinese Academy of Sciences, Beijing, China.

  • dx.doi.org/10.1124/dmd.113.052217.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (10)
Drug Metabolism and Disposition
Vol. 41, Issue 10
1 Oct 2013
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Research ArticleSpecial Section on Epigenetic Regulation of Drug Metabolizing Enzymes and Transporters

Role of Multiple MicroRNAs in Cyp2b9 Sex-Biased Expression

Xiaofeng Xie, Lingling Miao, Jun Yao, Chenchen Feng, Chenggang Li, Man Gao, Mingxia Liu, Likun Gong, Yizheng Wang, Xinming Qi and Jin Ren
Drug Metabolism and Disposition October 1, 2013, 41 (10) 1732-1737; DOI: https://doi.org/10.1124/dmd.113.052217

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Research ArticleSpecial Section on Epigenetic Regulation of Drug Metabolizing Enzymes and Transporters

Role of Multiple MicroRNAs in Cyp2b9 Sex-Biased Expression

Xiaofeng Xie, Lingling Miao, Jun Yao, Chenchen Feng, Chenggang Li, Man Gao, Mingxia Liu, Likun Gong, Yizheng Wang, Xinming Qi and Jin Ren
Drug Metabolism and Disposition October 1, 2013, 41 (10) 1732-1737; DOI: https://doi.org/10.1124/dmd.113.052217
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