Abstract
RationaleEnvironmental exposures strongly influence the development and progression of asthma. We have previously demonstrated that mice exposed to a diet enriched with methyl donors during vulnerable periods of fetal development can enhance the heritable risk of allergic airway disease through epigenetic changes. There is conflicting evidence on the role of folate (one of the primary methyl donors) in modifying allergic airway disease.ObjectivesWe hypothesized that blocking folate metabolism through the loss of methylene-tetrahydrofolate reductase (Mthfr) activity would reduce the allergic airway disease phenotype through epigenetic mechanisms.MethodsAllergic airway disease was induced in C57BL/6 and C57BL/6Mthfr-/- mice through house dust mite (HDM) exposure. Airway inflammation and airway hyperresponsiveness (AHR) were measured between the two groups. Gene expression and methylation profiles were generated for whole lung tissue. Disease and molecular outcomes were evaluated in C57BL/6 and C57BL/6Mthfr-/- mice supplemented with betaine.Measurements and main resultsLoss of Mthfr alters single carbon metabolite levels in the lung and serum including elevated homocysteine and cystathionine and reduced methionine. HDM-treated C57BL/6Mthfr-/- mice demonstrated significantly less airway hyperreactivity (AHR) compared to HDM-treated C57BL/6 mice. Furthermore, HDM-treated C57BL/6Mthfr-/- mice compared to HDM-treated C57BL/6 mice have reduced whole lung lavage (WLL) cellularity, eosinophilia, and Il-4/Il-5 cytokine concentrations. Betaine supplementation reversed parts of the HDM-induced allergic airway disease that are modified by Mthfr loss. 737 genes are differentially expressed and 146 regions are differentially methylated in lung tissue from HDM-treated C57BL/6Mthfr-/- mice and HDM-treated C57BL/6 mice. Additionally, analysis of methylation/expression relationships identified 503 significant correlations.ConclusionCollectively, these findings indicate that the loss of folate as a methyl donor is a modifier of allergic airway disease, and that epigenetic and expression changes correlate with this modification. Further investigation into the mechanisms that drive this observation is warranted.
Highlights
The prevalence of asthma has been increasing over the past several decades [1, 2], and currently, 12.9% of the United States population have been diagnosed with asthma [3]
Betaine supplementation reversed parts of the HDMinduced allergic airway disease that are modified by methylene-tetrahydrofolate reductase (Mthfr) loss. 737 genes are differentially expressed and 146 regions are differentially methylated in lung tissue from house dust mite (HDM)-treated
Analysis of methylation/ expression relationships identified 503 significant correlations. These findings indicate that the loss of folate as a methyl donor is a modifier of allergic airway disease, and that epigenetic and expression changes correlate with this modification
Summary
The prevalence of asthma has been increasing over the past several decades [1, 2], and currently, 12.9% of the United States population have been diagnosed with asthma [3]. Epigenetic mechanisms are the biological processes that lead to heritable changes in gene expression [14, 15] which are important for cell differentiation, X-chromosome inactivation, genomic imprinting, and other vital cellular responses [14]. Many of these epigenetic processes are dependent on the availability of methyl groups from S-adenosyl methionine (SAM). Single carbon metabolism is the metabolic pathway that maintains SAM levels in the cell (Fig 1A) This includes the re-methylation of homocysteine to methionine with either the co-substrate 5-methyltetrahydrofolate or betaine. An imbalance in single carbon metabolism can lead to changes in downstream methylation [16, 17], as well as changes in allergic airway disease (unpublished data)
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