Repression of IP-10 by Interactions between Histone Deacetylation and Hypermethylation in Idiopathic Pulmonary Fibrosis

Abstract

Targeted repression of a subset of key genes involved in tissue remodeling is a cardinal feature of idiopathic pulmonary fibrosis (IPF). The mechanism is unclear but is potentially important in disease pathogenesis and therapeutic targeting. We have previously reported that defective histone acetylation is responsible for the repression of the antifibrotic cyclooxygenase-2 gene. Here we extended our study to the repression of another antifibrotic gene, the potent angiostatic chemokine gamma interferon (IFN-␥)-inducible protein of 10 kDa (IP-10), in lung fibroblasts from patients with IPF. We revealed that this involved not only histone deacetylation, as with cyclooxygenase-2 repression, but also histone H3 hypermethylation, as a result of decreased recruitment of histone acetyltransferases and increased presence of histone deacetylase (HDAC)-containing repressor complexes, histone methyltransferases G9a and SUV39H1, and heterochromatin protein 1 at the IP-10 promoter, leading to reduced transcription factor binding. More importantly, treatment of diseased cells with HDAC or G9a inhibitors similarly reversed the repressive histone deacetylation and hypermethylation and restored IP-10 expression. These findings strongly suggest that epigenetic dysregulation involving interactions between histone deacetylation and hypermethylation is responsible for targeted repression of IP-10 and potentially other antifibrotic genes in fibrotic lung disease and that this is amenable to therapeutic targeting.

Hallmarks of the ageing lung

“…Epigenetic regulation via miRNA has recently been extended to the altered expression of the DNA methylase DNMT-1 in IPF [216]. In accordance with these data, there is also evidence for altered DNA methylation in IPF lungs: epigenome analysis revealed globally altered methylation patterns of hundreds of CpG islands, but also of specific promoters of genes implicated in lung fibrosis, which correlated with altered expression of the respective genes [217][218][219][220][221]. In addition to DNA methylation, epigenetic histone modifications, in particular those mediated by HDACs, may contribute to lung fibrosis, as they were shown to regulate expression of single target genes of pulmonary fibrosis [220,222].…”

γδ T Cells Attenuate Bleomycin-Induced Fibrosis through the Production of CXCL10

“…These data are supported by data from human IPF tissues in which fibroblasts cultured from IPF samples have decreased levels of CXCL10 compared with non-IPF tissues because of epigenetic dysregulation. 45 Our own in silico analysis of the public Gene Expression Omnibus database (GDS1252) found that the genes for TCRg, TCRd, and CXCL10 are all expressed in the tissues of patients with IPF. However, these data do not offer any insight into the functionality of ␥␦ T cells and CXCL10 in humans.…”

Epigenetic Regulation of MicroRNAs Controlling CLDN14 Expression as a Mechanism for Renal Calcium Handling

“…To systematically screen for the epigenetic effects on CLDN14 gene expression, we treated the primary cultures of mouse TALH cells (freshly isolated from the C57BL/6 mice described before) 9,10 in vitro for 16 hours with the DNA methyltransferase inhibitor 5-Aza-29-deoxycytidine, the histone-lysine methyltransferase inhibitor BIX 01294, 24 the histone demethylase inhibitor tranylcypromine, 25 and the HDAC inhibitors trichostatin A (TsA) and suberanilohydroxamic acid 26 (SAHA; approved by the Food and Drug Administration as Vorinostat). 5-Aza-29-deoxycytidine, BIX 01294, and tranylcypromine were without significant effects on claudin-14 mRNA levels (Supplemental Figure 1).…”