Epigenetics of idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a complex lung disease of unknown etiology. Development of IPF is influenced by both genetic and environmental factors. Recent work by our and other groups has identified strong genetic predisposition factors for the development of pulmonary fibrosis, and cigarette smoke remains the most strongly associated environmental exposure risk factor. Gene expression profiling studies of IPF lung have taught us quite a bit about the biology of this fatal disease, and those of peripheral blood have provided important biomarkers. However, epigenetic marks may be the missing link that connects the environmental exposure in genetically predisposed individuals to transcriptional changes associated with disease development. Moreover, epigenetic marks represent a promising therapeutic target for IPF. In this review, the disease is introduced, genetic and gene expression studies in IPF are summarized, exposures relevant to IPF and known epigenetic changes associated with cigarette smoke exposure are discussed, and epigenetic studies conducted so far in IPF are summarized. Limitations, challenges, and future opportunities in this field are also discussed.

Figure 1

An overview of epigenetic regulation of gene expression in IPF lung. Environmental exposures such as cigarette smoke influence epigenetic marks which in turn regulate gene expression. It is feasible that exposures influence gene expression by other mechanisms. Similarly, underlying genetic variation (asterisk) can regulate gene expression by affecting epigenetic marks or by other mechanisms (alteration of transcription factor binding sites, for example). Alterations in epigenetic marks have consequences on expression of key genes and pathways (Table 1) that lead to the clinical presentation, radiological (top panel) and pathologic (middle and bottom panels; fibroblastic foci [ff] and microscopic honeycoming [m]) features of IPF.