pdf: In utero supplementation with methyl donors enhances allergic airway disease in mice.

[Guest guest]

In utero supplementation with methyl donors enhances allergic airway

disease in mice.

Hollingsworth JW et al

J Clin Invest. 2008 Sep 18. [Epub ahead of print]

http://www.jci.org/articles/view/34378

Asthma is a complex heritable disease that is increasing in prevalence

and severity, particularly in developed countries such as the United

States, where 11% of the population is affected. The contribution of

environmental and genetic factors to this growing epidemic is currently

not well understood. We developed the hypothesis, based on previous

literature, that changes in DNA methylation resulting in aberrant gene

transcription may enhance the risk of developing allergic airway

disease. Our findings indicate that in mice, a maternal diet

supplemented with methyl donors enhanced the severity of allergic airway

disease that was inherited transgenerationally. Using a genomic

approach, we discovered 82 gene-associated loci that were differentially

methylated after in utero supplementation with a methyl-rich diet. These

methylation changes were associated with decreased transcriptional

activity and increased disease severity. Runt-related transcription

factor 3 (Runx3), a gene known to negatively regulate allergic airway

disease, was found to be excessively methylated, and Runx3 mRNA and

protein levels were suppressed in progeny exposed in utero to a

high-methylation diet. Moreover, treatment with a demethylating agent

increased Runx3 gene transcription, further supporting our claim that a

methyl-rich diet can affect methylation status and consequent

transcriptional regulation. Our findings indicate that dietary factors

can modify the heritable risk of allergic airway disease through

epigenetic mechanisms during a vulnerable period of fetal development in

mice.

PMID: 18802477

Hollingsworth JW, Maruoka S, Boon K, Garantziotis S, Li Z, Tomfohr J,

N, Potts EN, Whitehead G, Brass DM, Schwartz DA.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of

Medicine, Duke University Medical Center, Durham, North Carolina, USA.

Environmental Lung Disease Laboratory, National Heart Lung and Blood

Institute, Research Triangle Park, North Carolina, USA. Office of Cancer

Genomics, National Cancer Institute, Bethesda, land, USA. Laboratory

of Respiratory Biology, National Institute of Environmental Health

Sciences, Research Triangle Park, North Carolina, USA.

Neonatal-Perinatal Research Institute, Duke University Medical Center,

Durham, North Carolina, USA. Division of Pulmonary and Critical Care

Medicine, Department of Medicine, National Jewish Health, Denver,

Colorado, USA.