Original Article

A methyl-deficient diet modifies histone methylation and alters Igf2 and H19 repression in the prostate

  1. Joseph R. Dobosy1,
  2. Vivian X. Fu1,
  3. Joshua A. Desotelle1,
  4. Rajini Srinivasan2,3,
  5. Michelle L. Kenowski1,
  6. Nima Almassi1,
  7. Richard Weindruch4,5,
  8. John Svaren3,5,
  9. David F. Jarrard1,5,6,*

Article first published online: 5 MAY 2008

DOI: 10.1002/pros.20782

Issue

The Prostate

The Prostate

Volume 68, Issue 11, pages 1187–1195, 1 August 2008

Additional Information

How to Cite

Dobosy, J. R., Fu, V. X., Desotelle, J. A., Srinivasan, R., Kenowski, M. L., Almassi, N., Weindruch, R., Svaren, J. and Jarrard, D. F. (2008), A methyl-deficient diet modifies histone methylation and alters Igf2 and H19 repression in the prostate. The Prostate, 68: 1187–1195. doi: 10.1002/pros.20782

Author Information

  1. 1

    Environmental and Molecular Toxicology, University of Wisconsin, Madison, Wisconsin

  2. 2

    Department of Genetics, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin

  3. 3

    Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin

  4. 4

    Department of Medicine and the Veterans Administration Geriatric Research Education and Clinical Center, University of Wisconsin, Madison, Wisconsin

  5. 5

    University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin

  6. 6

    Department of Surgery, University of Wisconsin, Madison, Wisconsin

*K6/527 University of Wisconsin Clinical Science Center, 600 Highland Avenue, Madison, WI 53792.

Publication History

  1. Issue published online: 17 JUN 2008
  2. Article first published online: 5 MAY 2008
  3. Manuscript Accepted: 1 APR 2008
  4. Manuscript Received: 7 FEB 2008

Funded by

  • National Institutes of Health. Grant Number: R01CA97131
  • University of Wisconsin George M. O'Brien Urology Research Center. Grant Number: 1P50DK065303
  • John Livesey Endowment

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Keywords:

  • prostate cancer;
  • methylation;
  • IGF2;
  • epigenetics;
  • histone modification

Abstract

Background

Folate and methyl-group deficiency has been linked to prostate cancer susceptibility, yet the mechanisms underlying these observations are incompletely understood. The region of the genome containing the imprinted genes insulin-like growth factor 2 (Igf2) and H19, both of which display oncogenic functions, may be particularly sensitive to environmental influences.

Methods

To determine whether a methyl-deficient diet impacts epigenetic controls at the Igf2–H19 locus, we placed C57BL/6 mice containing a polymorphism at the imprinted Igf2–H19 locus on a choline and methionine deficient (CMD) diet. We interrogated this locus for expression and epigenetic changes in prostate tissues.

Results

A significant increase in both Igf2 and H19 expression was found in CMD prostate tissues compared to controls. These expression changes were reversible with shorter exposure to the CMD diet. Chromatin immunoprecipitation (ChIP) revealed significant decreases in repressive histone modifications (dimethyl-H3K9) within the H19 promoter, as well as Igf2 P2 and P3 promoters. DNA methylation within these promoters was not altered. No significant change in Igf2 or H19 imprinting was observed.

Conclusions

These findings highlight the plasticity of the epigenome in an epithelial organ vulnerable to neoplastic change. They further suggest that chromatin modifications are more susceptible to methyl-deficient diets than DNA methylation at this locus. Prostate 68: 1187–1195, 2008. © 2008 Wiley-Liss, Inc.

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