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Identification of nuclear hormone receptor pathways causing insulin resistance by transcriptional and epigenomic analysis

Nature Cell Biology volume 17, pages 4456 (2015) | Download Citation

Abstract

Insulin resistance is a cardinal feature of Type 2 diabetes (T2D) and a frequent complication of multiple clinical conditions, including obesity, ageing and steroid use, among others. How such a panoply of insults can result in a common phenotype is incompletely understood. Furthermore, very little is known about the transcriptional and epigenetic basis of this disorder, despite evidence that such pathways are likely to play a fundamental role. Here, we compare cell autonomous models of insulin resistance induced by the cytokine tumour necrosis factor-α or by the steroid dexamethasone to construct detailed transcriptional and epigenomic maps associated with cellular insulin resistance. These data predict that the glucocorticoid receptor and vitamin D receptor are common mediators of insulin resistance, which we validate using gain- and loss-of-function studies. These studies define a common transcriptional and epigenomic signature in cellular insulin resistance enabling the identification of pathogenic mechanisms.

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Acknowledgements

We would like to thank M. Herman (Beth Israel Deaconess Medical Center, USA) for providing adipose RNA from obese mice. We thank members of the Rosen laboratory for helpful discussions, and E. Merkel for technical assistance. The V729I and D641V GR mutant alleles were from G. Chrousos (Athens University Medical School, Greece), and the N768 allele was a gift from K. Yamamoto (University of California, San Francisco, USA). J-C. Wang (University of California, Berkeley, USA) provided the anti-GR antibody used for ChIP-PCR and ChIP-Seq, and he and I. Rogatsky were generous with their time and advice. This work was supported by NIH Roadmap grant R01 ES017690, R01085171 and an American Diabetes Association Career Development Award to E.D.R., NIH Innovator grant DP2OD007447 to B.A.G., and by American Heart Association Postdoctoral Awards to S.K. and L.T.T.

Author information

Author notes

    • Sona Kang
    •  & Linus T. Tsai

    These authors contributed equally to this work.

Affiliations

  1. Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA

    • Sona Kang
    • , Linus T. Tsai
    • , Yiming Zhou
    • , Su Xu
    • , Michael J. Griffin
    •  & Evan D. Rosen
  2. Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA

    • Adam Evertts
  3. Broad Institute, Cambridge, Massachusetts 02142, USA

    • Robbyn Issner
    • , Holly J. Whitton
    • , Charles B. Epstein
    • , Tarjei S. Mikkelsen
    •  & Evan D. Rosen
  4. Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Benjamin A. Garcia
  5. Harvard Medical School, Boston, Massachusetts 02215, USA

    • Evan D. Rosen

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Contributions

S.K., L.T.T. and E.D.R. designed the study. Experimental work was carried out by S.K., with help from M.J.G. and S.X.; ChIP-Seq was performed by S.K. and L.T.T. with assistance from R.I., H.J.W. and C.B.E. Computational data analysis was performed by L.T.T., Y.Z. and T.S.M. A.E. and B.A.G. performed histone mass spectrometry. S.K., L.T.T. and E.D.R. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Evan D. Rosen.

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https://doi.org/10.1038/ncb3080

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