A methyl-deficient diet modifies histone methylation and alters Igf2 and H19 repression in the prostate.
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.
Dobosy
Joseph R
JR
Environmental and Molecular Toxicology, University of Wisconsin, Madison, Wisconsin 53792, USA.
Fu
Vivian X
VX
Desotelle
Joshua A
JA
Srinivasan
Rajini
R
Kenowski
Michelle L
ML
Almassi
Nima
N
Weindruch
Richard
R
Svaren
John
J
Jarrard
David F
DF
D000821:Animal Feed; D000818:Animals; D001835:Body Weight; D002796:Choline Deficiency / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000502:physiology; D018392:Genomic Imprinting / Q000502:physiology; D006657:Histones / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000172:deficiency*; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D009929:Organ Size; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000502:physiology; D011467:Prostate / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics* / Q000378:metabolism; D012669:Seminal Vesicles / Q000166:cytology
C094335:H19 long non-coding RNA; D006657:Histones; C513121:IGF2 protein, mouse; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D007335:Insulin-Like Growth Factor II; D008715:Methionine