Non-Canonical Regulation of Type I Collagen through Promoter Binding of SOX2 and Its Contribution to Ameliorating Pulmonary Fibrosis by Butylidenephthalide
Pulmonary fibrosis is a fatal respiratory disease that gradually leads to dyspnea, mainly accompanied by excessive collagen production in the fibroblast and myofibroblast through mechanisms such as abnormal alveolar epithelial cells remodeling and stimulation of the extracellular matrix (ECM). Our r...
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2018-10-01
|
Series: | International Journal of Molecular Sciences |
Subjects: | |
Online Access: | http://www.mdpi.com/1422-0067/19/10/3024 |
id |
doaj-5554c8c987c1422ea683dcb71f95b733 |
---|---|
record_format |
Article |
spelling |
doaj-5554c8c987c1422ea683dcb71f95b7332020-11-24T23:42:45ZengMDPI AGInternational Journal of Molecular Sciences1422-00672018-10-011910302410.3390/ijms19103024ijms19103024Non-Canonical Regulation of Type I Collagen through Promoter Binding of SOX2 and Its Contribution to Ameliorating Pulmonary Fibrosis by ButylidenephthalideHong-Meng Chuang0Li-Ing Ho1Mao-Hsuan Huang2Kun-Lun Huang3Tzyy-Wen Chiou4Shinn-Zong Lin5Hong-Lin Su6Horng-Jyh Harn7Buddhist Tzu Chi Bioinnovation Center, Tzu Chi Foundation, Hualien 970, TaiwanDivision of Respiratory Therapy, Department of Chest Medicine, Taipei Veterans General Hospital, Taipei 112, TaiwanBuddhist Tzu Chi Bioinnovation Center, Tzu Chi Foundation, Hualien 970, TaiwanHyperbaric Oxygen Therapy Center, Division of Pulmonary and Critical Care Medicine, Graduate Institute of Aerospace and Undersea Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, TaiwanDepartment of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien 974, TaiwanBuddhist Tzu Chi Bioinnovation Center, Tzu Chi Foundation, Hualien 970, TaiwanDepartment of Life Sciences, Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, TaiwanBuddhist Tzu Chi Bioinnovation Center, Tzu Chi Foundation, Hualien 970, TaiwanPulmonary fibrosis is a fatal respiratory disease that gradually leads to dyspnea, mainly accompanied by excessive collagen production in the fibroblast and myofibroblast through mechanisms such as abnormal alveolar epithelial cells remodeling and stimulation of the extracellular matrix (ECM). Our results show that a small molecule, butylidenephthalide (BP), reduces type I collagen (COL1) expression in Transforming Growth Factor beta (TGF-β)-induced lung fibroblast without altering downstream pathways of TGF-β, such as Smad phosphorylation. Treatment of BP also reduces the expression of transcription factor Sex Determining Region Y-box 2 (SOX2), and the ectopic expression of SOX2 overcomes the inhibitory actions of BP on COL1 expression. We also found that serial deletion of the SOX2 binding site on 3′COL1 promoter results in a marked reduction in luciferase activity. Moreover, chromatin immunoprecipitation, which was found on the SOX2 binding site of the COL1 promoter, decreases in BP-treated cells. In an in vivo study using a bleomycin-induced pulmonary fibrosis C57BL/6 mice model, mice treated with BP displayed reduced lung fibrosis and collagen deposition, recovering in their pulmonary ventilation function. The reduction of SOX2 expression in BP-treated lung tissues is consistent with our findings in the fibroblast. This is the first report that reveals a non-canonical regulation of COL1 promoter via SOX2 binding, and contributes to the amelioration of pulmonary fibrosis by BP treatment.http://www.mdpi.com/1422-0067/19/10/3024pulmonary fibrosisbutylidenephthalideSOX2type I collagenbleomycin |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hong-Meng Chuang Li-Ing Ho Mao-Hsuan Huang Kun-Lun Huang Tzyy-Wen Chiou Shinn-Zong Lin Hong-Lin Su Horng-Jyh Harn |
spellingShingle |
Hong-Meng Chuang Li-Ing Ho Mao-Hsuan Huang Kun-Lun Huang Tzyy-Wen Chiou Shinn-Zong Lin Hong-Lin Su Horng-Jyh Harn Non-Canonical Regulation of Type I Collagen through Promoter Binding of SOX2 and Its Contribution to Ameliorating Pulmonary Fibrosis by Butylidenephthalide International Journal of Molecular Sciences pulmonary fibrosis butylidenephthalide SOX2 type I collagen bleomycin |
author_facet |
Hong-Meng Chuang Li-Ing Ho Mao-Hsuan Huang Kun-Lun Huang Tzyy-Wen Chiou Shinn-Zong Lin Hong-Lin Su Horng-Jyh Harn |
author_sort |
Hong-Meng Chuang |
title |
Non-Canonical Regulation of Type I Collagen through Promoter Binding of SOX2 and Its Contribution to Ameliorating Pulmonary Fibrosis by Butylidenephthalide |
title_short |
Non-Canonical Regulation of Type I Collagen through Promoter Binding of SOX2 and Its Contribution to Ameliorating Pulmonary Fibrosis by Butylidenephthalide |
title_full |
Non-Canonical Regulation of Type I Collagen through Promoter Binding of SOX2 and Its Contribution to Ameliorating Pulmonary Fibrosis by Butylidenephthalide |
title_fullStr |
Non-Canonical Regulation of Type I Collagen through Promoter Binding of SOX2 and Its Contribution to Ameliorating Pulmonary Fibrosis by Butylidenephthalide |
title_full_unstemmed |
Non-Canonical Regulation of Type I Collagen through Promoter Binding of SOX2 and Its Contribution to Ameliorating Pulmonary Fibrosis by Butylidenephthalide |
title_sort |
non-canonical regulation of type i collagen through promoter binding of sox2 and its contribution to ameliorating pulmonary fibrosis by butylidenephthalide |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2018-10-01 |
description |
Pulmonary fibrosis is a fatal respiratory disease that gradually leads to dyspnea, mainly accompanied by excessive collagen production in the fibroblast and myofibroblast through mechanisms such as abnormal alveolar epithelial cells remodeling and stimulation of the extracellular matrix (ECM). Our results show that a small molecule, butylidenephthalide (BP), reduces type I collagen (COL1) expression in Transforming Growth Factor beta (TGF-β)-induced lung fibroblast without altering downstream pathways of TGF-β, such as Smad phosphorylation. Treatment of BP also reduces the expression of transcription factor Sex Determining Region Y-box 2 (SOX2), and the ectopic expression of SOX2 overcomes the inhibitory actions of BP on COL1 expression. We also found that serial deletion of the SOX2 binding site on 3′COL1 promoter results in a marked reduction in luciferase activity. Moreover, chromatin immunoprecipitation, which was found on the SOX2 binding site of the COL1 promoter, decreases in BP-treated cells. In an in vivo study using a bleomycin-induced pulmonary fibrosis C57BL/6 mice model, mice treated with BP displayed reduced lung fibrosis and collagen deposition, recovering in their pulmonary ventilation function. The reduction of SOX2 expression in BP-treated lung tissues is consistent with our findings in the fibroblast. This is the first report that reveals a non-canonical regulation of COL1 promoter via SOX2 binding, and contributes to the amelioration of pulmonary fibrosis by BP treatment. |
topic |
pulmonary fibrosis butylidenephthalide SOX2 type I collagen bleomycin |
url |
http://www.mdpi.com/1422-0067/19/10/3024 |
work_keys_str_mv |
AT hongmengchuang noncanonicalregulationoftypeicollagenthroughpromoterbindingofsox2anditscontributiontoamelioratingpulmonaryfibrosisbybutylidenephthalide AT liingho noncanonicalregulationoftypeicollagenthroughpromoterbindingofsox2anditscontributiontoamelioratingpulmonaryfibrosisbybutylidenephthalide AT maohsuanhuang noncanonicalregulationoftypeicollagenthroughpromoterbindingofsox2anditscontributiontoamelioratingpulmonaryfibrosisbybutylidenephthalide AT kunlunhuang noncanonicalregulationoftypeicollagenthroughpromoterbindingofsox2anditscontributiontoamelioratingpulmonaryfibrosisbybutylidenephthalide AT tzyywenchiou noncanonicalregulationoftypeicollagenthroughpromoterbindingofsox2anditscontributiontoamelioratingpulmonaryfibrosisbybutylidenephthalide AT shinnzonglin noncanonicalregulationoftypeicollagenthroughpromoterbindingofsox2anditscontributiontoamelioratingpulmonaryfibrosisbybutylidenephthalide AT honglinsu noncanonicalregulationoftypeicollagenthroughpromoterbindingofsox2anditscontributiontoamelioratingpulmonaryfibrosisbybutylidenephthalide AT horngjyhharn noncanonicalregulationoftypeicollagenthroughpromoterbindingofsox2anditscontributiontoamelioratingpulmonaryfibrosisbybutylidenephthalide |
_version_ |
1725503228402991104 |