Repression of IP-10 by interactions between histone deacetylation and hypermethylation in idiopathic pulmonary fibrosis.
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-gamma)-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.
Coward
William R
WR
Division of Respiratory Medicine, Centre for Respiratory Research and Nottingham Respiratory Biomedical Research Unit, University of Nottingham, Clinical Sciences Building, City Hospital, Nottingham NG5 1PB, United Kingdom.
Watts
Keira
K
Feghali-Bostwick
Carol A
CA
Jenkins
Gisli
G
Pang
Linhua
L
D000107:Acetylation / Q000187:drug effects; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism*; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology; D051548:Histone Acetyltransferases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism*; D008745:Methylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D002868:Chromosomal Proteins, Non-Histone; D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D000090266:Chromobox Protein Homolog 5; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases
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