DNA methylomic changes in fibroblasts of idiopathic pulmonary fibrosis (IPF)
IPF is a devastating and progressive scarring disease of the lung, and our laboratory focuses on understanding how fibroblasts, the main effector cell in fibrosis, differ in phenotype between normal lung and those derived from the lungs of IPF patients. We have discovered that many of these differences in cellular function and gene expression can be attributed to differences in DNA methylation. We are now characterizing how the DNA methylomic patterns in fibroblasts differ among IPF patients of varying severity. Our goal is to determine whether DNA methylation changes account for, and ultimately predict, the variability in disease progression.
Gene specific DNA methylation changes in IPF fibroblasts
In addition to whole genomic DNA methylomic patterning, we also study how DNA methylation changes occur at the individual gene level, and how alterations in expression of these genes may contribute to IPF pathogenesis. Several candidate genes have been shown to be significantly hyper- or hypomethylated in IPF fibroblasts and we are investigating the functional consequence of these DNA methylation changes. In particular, CDKN2B, a cell cycle inhibitor that regulates proliferation and differentiation, was found to be significantly hypermethylated in IPF cells and we are using animal models and in vitro studies to examine the function and relevance of this gene to IPF.
Regulation of DNA methyltransferases (DNMT) and DNA methylomic patterns in lung fibroblasts
DNMTs catalyze the addition of methyl groups to DNA and our laboratory is currently investigating how DNMT activity is regulated in lung fibroblasts. Transforming growth factor beta and prostaglandin E2 are two well-recognized pro- and anti-fibrotic mediators, respectively, and our lab investigates how these mediators modulate the expression of DNMTs and ultimately, the pattern of DNA methylation in mesenchymal cells. We believe these studies will provide novel insights into how critical, soluble mediators in the lung regulate DNA methylation patterns in both homeostasis and disease.
DNA methylation changes in asthmatics in China exposed to air pollution
As part of the University of Michigan-Peking University Joint Institute, we are investigating how air pollution in Beijing, China affects the DNA methylation patterns of patients with asthma. In this pilot project grant with collaborator Yahong Chen, MD from Peking University, we are longitudinally following Chinese adults with asthma and determining whether the DNA methylation levels of certain inflammatory genes vary throughout the year, correlating with changing levels of air pollution.