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Epigenetic Regulation in Asthma


Asthma is the most common chronic childhood disease, affecting 9 million children in the United States. This disease is increasing in prevalence, incidence, and severity, particularly in developed countries.  Asthma is a strongly familial condition, with estimates of heritability ranging from 36 – 79%.  Although genetic factors unquestionably play a role in the development of asthma and atopy, the environmental factors to which children are exposed in utero and postnatally are also of considerable importance. The overall hypothesis of our work is that epigenetic mechanisms play a fundamental role in the etiology of asthma by modulating transcriptional activity of critical genes that affect immune maturation through alterations in DNA methylation and chromatin modification status, and this then leads to the development of asthma.

Methylation of CpG islands within regulatory regions of DNA is an important epigenetic mechanism controlling transcriptional activity, with the level of CpG methylation within specific genetic regions being heritable. It has been demonstrated that the concentration of methyl donors in the diet of pregnant agouti mice has transgenerational effects on coat color of the progeny due to altered expression of the agouti gene, a result of methylation of the agouti promoter. Emerging research indicates that epigenetic mechanisms affect the expression of transcription factors that control the lineage of Th1, Th2, and Treg cells. 

Click the image to see Figure 5
Figure 5

One of the approaches we are taking in our laboratory is to study the role in utero diet and environmental exposures play in the development of allergic airway disease in mice, to study how DNA methylation is altered by these exposures in specific immune cell types and, and how these changes consequently lead to the development of allergic airway disease. Our recently published findings indicated that in mice, a maternal diet supplemented with methyl-donors enhanced the severity of allergic airway disease that was inherited trans-generationally. Using methylation-specific digital karyotyping (MSDK), we discovered 82 gene-associated loci that were differentially methylated after in utero supplementation with a methyl-rich diet rich.  This study provided the first in vivo evidence that in utero diet can impact CpG methylation and trans-generational inheritance of allergic airway disease.

Click the image to see Figure 6
Figure 6

We are currently pursuing other in utero diets and exposures (folate concentrations, environmental tobacco smoke etc) and alternative, more comprehensive genome-wide approaches to study DNA methylation. We are studying the role of epigenetic marks in the maturation of specific immune cell populations that have been shown to play a role in human asthma. 

Click the image to see Figure 7
Figure 7

In addition to the murine studies, we are examining DNA methylation patterns in children with asthma. We are conducting a number of studies to elucidate the role of DNA methylation in cohorts of children with asthma who are exposed to different environmental factors (rural farming exposure, inner city exposures etc).  In addition to the influence of exposures, we plan on examining genetic factors, namely DNA sequence changes, that influence epigenetic marks.

 

Asthma Epigenetics Publications

1. Yang IV, Tomfohr J, Singh J, Foss CM, Marshall HE, Que LG, McElvania-Tekippe E, Florence S, Sundy JS, Schwartz DA. Gene Expression in the Lung is Influenced by Disease State in Allergic Asthma. Am J Respir Crit Care Med. 2012 Jan 12. [Epub ahead of print]

2. Yang IV and Schwartz DA.  Epigenetic Control of Gene Expression in the Lung.  Am J Resp Crit Care Med. 2011;183:1295-301. PMID: 21720866

3. Schwartz DA. Epigenetics and environmental lung disease. Proc Am Thorac Soc. 2010 May;7(2):123-5. Review.

4. Boon K, Tomfohr JK, Bailey NW, Garantziotis S, Li Z, Brass DM, Maruoka S, Hollingsworth JW, Schwartz DA. Evaluating genome-wide DNA methylation changes in mice by Methylation Specific Digital Karyotyping.  BMC Genomics 2008; 9:598.

5. Hollingsworth JW, Maruoka S, Boon K, Brass DM, Tomfohr J, Garantziotis S, Li Z, Bailey N, Potts E, Schwartz DA.  In utero supplementation with methyl-donors enhances allergic airway disease in mice.  J Clin Invest 2008; 118:3462-3469.