Altered DNA Methylation Profile in Idiopathic Pulmonary Fibrosis

Sanders, Yan Y.; Ambalavanan, Namasivayam; Halloran, Brian; Zhang, Xiangyu; Liu, Hui; Crossman, David K.; Bray, Molly; Zhang, Kui; Thannickal, Victor J.; Hagood, James S.

doi:10.1164/rccm.201201-0077oc

Cited by 192 publications

(147 citation statements)

References 51 publications

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“…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].…”

Section: Epigenetic Alterationsmentioning

confidence: 64%

Hallmarks of the ageing lung

2015

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Ageing is the main risk factor for major non-communicable chronic lung diseases, including chronic obstructive pulmonary disease, most forms of lung cancer and idiopathic pulmonary fibrosis. While the prevalence of these diseases continually increases with age, their respective incidence peaks at different times during the lifespan, suggesting specific effects of ageing on the onset and/or pathogenesis of chronic obstructive pulmonary disease, lung cancer and idiopathic pulmonary fibrosis. Recently, the nine hallmarks of ageing have been defined as cell-autonomous and non-autonomous pathways involved in ageing. Here, we review the available evidence for the involvement of each of these hallmarks in the pathogenesis of chronic obstructive pulmonary disease, lung cancer, or idiopathic pulmonary fibrosis. Importantly, we propose an additional hallmark, "dysregulation of the extracellular matrix", which we argue acts as a crucial modifier of cell-autonomous changes and functions, and as a key feature of the above-mentioned lung diseases. @ERSpublications Hallmarks of ageing are selecting factors for the pathogenesis of COPD, lung cancer and IPF

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Section: Epigenetic Alterationsmentioning

confidence: 64%

Hallmarks of the ageing lung

2015

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“…the data do not support a simple inverse relationship of hypermethylation and reduced gene expression and hypomethylation with increased gene expression. This lack of predicted correlation, however, has also been observed in genome-wide analysis of lung parenchyma of subjects with idiopathic pulmonary fibrosis (37). Methylation along a gene, in a promoter region or in the gene per se, alone or in combination with other epigenetic changes, may directly or indirectly change the transcriptional output of a gene or genomic region (5).…”

Section: Discussionmentioning

confidence: 91%

Cigarette smoking induces small airway epithelial epigenetic changes with corresponding modulation of gene expression

Buro-Auriemma

Salit

Hackett

et al. 2013

Human Molecular Genetics

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The small airway epithelium (SAE), the first site of smoking-induced lung pathology, exhibits genome-wide changes in gene expression in response to cigarette smoking. Based on the increasing evidence that the epigenome can respond to external stimuli in a rapid manner, we assessed the SAE of smokers for genome-wide DNA methylation changes compared with nonsmokers, and whether changes in SAE DNA methylation were linked to the transcriptional output of these cells. Using genome-wide methylation analysis of SAE DNA of nonsmokers and smokers, the data identified 204 unique genes differentially methylated in SAE DNA of smokers compared with nonsmokers, with 67% of the regions with differential methylation occurring within 2 kb of the transcriptional start site. Among the genes with differential methylation were those related to metabolism, transcription, signal transduction and transport. For the differentially methylated genes, 35 exhibited a correlation with gene expression, 54% with an inverse correlation of DNA methylation with gene expression and 46% a direct correlation. These observations provide evidence that cigarette smoking alters the DNA methylation patterning of the SAE and that, for some genes, these changes are associated with the smoking-related changes in gene expression.

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“…Quantitative methylation analysis was carried out as described previously [16] using OneStep qMethyl Kit (Zymo Research, Irvine, CA, USA) with some modifications.…”

Section: Dna Methylation Changes In Apoptosis-related Genesmentioning

confidence: 99%

“…We quantified DNA methylation changes at the promoter region of both genes using the OneStep qMethyl kit (Zymo Research), which quantifies locus-specific DNA methylation [16,23]. Following treatment with SAHA, Bak showed increases in unmethylated DNA, while Bcl-xL demonstrated decreases that correlate with the observed increased expression of Bak and decreased expression of Bcl-xL, respectively ( fig.…”

Section: Saha Alters the Expression Of Apoptosis-related Genes Bak Anmentioning

confidence: 99%

Histone deacetylase inhibition promotes fibroblast apoptosis and ameliorates pulmonary fibrosis in mice

Sanders

Hagood

Liu

et al. 2014

European Respiratory Journal

125

124

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Idiopathic pulmonary fibrosis (IPF) is a fatal disease, and therapeutic agents have shown only modest efficacy. Epigenetic alterations contribute to the pathogenesis of IPF. The histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), has been approved for clinical use in cancer; however, its potential efficacy in modulating fibroblast survival and lung fibrosis has not been extensively investigated.We investigated the effects of SAHA on apoptosis of primary IPF myofibroblasts and on injury-induced lung fibrosis in a murine model. SAHA-induced apoptosis of IPF myofibroblasts, an effect that was mediated, at least in part, by upregulation of the pro-apoptotic gene Bak and downregulation of the antiapoptotic gene Bcl-xL.Alterations in the expression of these apoptosis-related genes were associated with histone modifications and changes in DNA methylation. In addition to the expected higher levels of histone acetylation in treated cells, we also detected changes in other histone modifications, such as histone methylation. In a murine model of bleomycin-induced pulmonary fibrosis, SAHA-treated mice displayed decreased lung fibrosis and improved lung function compared to the bleomycin only group.These results suggest that histone deacetylase inhibitors may offer a new therapeutic strategy in IPF by modulating myofibroblast susceptibility to apoptosis. @ERSpublications HDACi SAHA induces IPF fibroblast apoptosis, modulates Bcl-2 family genes and ameliorates mice lung fibrosis

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Altered DNA Methylation Profile in Idiopathic Pulmonary Fibrosis

Cited by 192 publications

References 51 publications

Hallmarks of the ageing lung

Hallmarks of the ageing lung

Cigarette smoking induces small airway epithelial epigenetic changes with corresponding modulation of gene expression

Histone deacetylase inhibition promotes fibroblast apoptosis and ameliorates pulmonary fibrosis in mice

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