SUV39H1 Reduction Is Implicated in Abnormal Inflammation in COPD

Tzu-Tao Chen,Shu-Chuan Ho,Hsiao-Chi Chuang,Yao-Fei Chan,Wen-Te Liu,Sheng-Ming Wu,Ta-Chih Hsiao,Kang-Yun Lee,Chien-Ying Liu,Po-Hao Feng,Jer-Nan Juang,Kuan-Yuan Chen,Lu-Wei Kuo

doi:10.1038/srep46667

Abstract

Chronic obstructive pulmonary disease(COPD) is characterized by enhanced chronic inflammation in the airways, lung parenchyma, and circulation. We investigated whether SUV39H1, a histone methyltransferase, is causatively implicated in the abnormal inflammation observed in COPD. The SUV39H1 and H3K9me3 levels were reduced in peripheral blood mononuclear cells(PBMCs), primary human small airway epithelial cells(HSAEpCs) and lung tissues from COPD patients, which were correlated with poor lung function and the serum IL-8 and IL-6 levels. A specific SUV39H1 inhibitor, chaetocin, induced a distinct COPD panel of inflammatory cytokines in normal PBMCs. Mechanistically, chaetocin reduced the SUV39H1 and H3K9me3 levels in the native IL-8 promoter in normal HSAEpCs, which mimicked unstimulated COPD HSAEpCs and led to decreased HP-1α levels and increased RNA polymerase II levels. SUV39H1 knockdown reproduced the pattern of COPD inflammation, whereas SUV39H1 overexpression in COPD HSAEpCs rescued the H3K9me3 levels and suppressed inflammation. In COPD mice, chaetocin further repressed the SUV39H1/H3K9me3 levels and enhanced inflammation. SUV39H1 epigenetically controls a distinct panel of pro-inflammatory cytokines. Its reduction in COPD leads to a loss of the repressive chromatin mark H3K9me3 and confers an abnormal inflammatory response to stimulators. SUV39H1 and its regulatory pathways are potential therapeutic targets for COPD.

Highlights

Chronic obstructive airway disease (COPD) is a leading cause of morbidity and mortality worldwide[1]
peripheral blood mononuclear cells (PBMCs) were collected from normal healthy controls (NC), normal smoking subjects (NS), and patients with mild to severe Chronic obstructive pulmonary disease (COPD)
A previous report showed that IL-8, but not IL-6, appears to be a marker in normal smoking subjects[11], which suggests that smoking induces systemic IL-8 inflammation

Summary

Introduction

Chronic obstructive airway disease (COPD) is a leading cause of morbidity and mortality worldwide[1]. COPD focuses on the lung, but it has systemic manifestations, such as cardiovascular disease, lung cancer and other malignancies[7] These comorbidities increase the risk of hospitalization and mortality, which are major causes of death[8]. In the lungs of COPD patients, reductions in HDAC activity and HDAC2 expression are associated with increases in the IL-8 mRNA levels and histone-H4 acetylation at the promoter[13] These activity and expression effects contribute to glucocorticoid insensitivity[14]. H3K9me[3] mediates gene silencing by recruiting repressors and cofactors, including HDACs and heterochromatin protein-1α(HP1α)[19] This repressive chromatin mark has been identified as a promoter of a few LPS-inducible inflammatory genes in monocytes and dendritic cells[20,21]. The dysregulation of SUV39H1-H3K9me[3] has been reported as a major underlying mechanism for metabolic memory and the sustained pro-inflammatory phenotype of diabetic cell[23]

Methods

Results

Conclusion