Regardless of the hierarchical order of events, our observations support a central role for G9a- and EZH2-mediated histone hypermethylation and a model of bidirectional, mutually reinforcing, and interdependent crosstalk between histone hypermethylation and DNA methylation in the epigenetic silencing of COX-2 and potentially other antifibrotic genes in IPF (Fig. 9). Here, PTGS2 is linked to idiopathic pulmonary fibrosis.