8-Oxoguanine targeted by 8-oxoguanine DNA glycosylase 1 (OGG1) is central to fibrogenic gene activation upon lung injury
(2023) In Nucleic Acids Research 51(3). p.1087-1102- Abstract
Reactive oxygen species (ROS) are implicated in epithelial cell-state transition and deposition of extracellular matrix upon airway injury. Of the many cellular targets of ROS, oxidative DNA modification is a major driving signal. However, the role of oxidative DNA damage in modulation profibrotic processes has not been fully delineated. Herein, we report that oxidative DNA base lesions, 8-oxoG, complexed with 8-oxoguanine DNA glycosylase 1 (OGG1) functions as a pioneer factor, contributing to transcriptional reprogramming within airway epithelial cells. We show that TGFβ1-induced ROS increased 8-oxoG levels in open chromatin, dynamically reconfigure the chromatin state. OGG1 complexed with 8-oxoG recruits transcription factors,... (More)
Reactive oxygen species (ROS) are implicated in epithelial cell-state transition and deposition of extracellular matrix upon airway injury. Of the many cellular targets of ROS, oxidative DNA modification is a major driving signal. However, the role of oxidative DNA damage in modulation profibrotic processes has not been fully delineated. Herein, we report that oxidative DNA base lesions, 8-oxoG, complexed with 8-oxoguanine DNA glycosylase 1 (OGG1) functions as a pioneer factor, contributing to transcriptional reprogramming within airway epithelial cells. We show that TGFβ1-induced ROS increased 8-oxoG levels in open chromatin, dynamically reconfigure the chromatin state. OGG1 complexed with 8-oxoG recruits transcription factors, including phosphorylated SMAD3, to pro-fibrotic gene promoters thereby facilitating gene activation. Moreover, 8-oxoG levels are elevated in lungs of mice subjected to TGFβ1-induced injury. Pharmacologic targeting of OGG1 with the selective small molecule inhibitor of 8-oxoG binding, TH5487, abrogates fibrotic gene expression and remodeling in this model. Collectively, our study implicates that 8-oxoG substrate-specific binding by OGG1 is a central modulator of transcriptional regulation in response to tissue repair.
(Less)
- author
- organization
- publishing date
- 2023-02-22
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Nucleic Acids Research
- volume
- 51
- issue
- 3
- pages
- 16 pages
- publisher
- Oxford University Press
- external identifiers
-
- pmid:36651270
- scopus:85159961134
- ISSN
- 0305-1048
- DOI
- 10.1093/nar/gkac1241
- language
- English
- LU publication?
- yes
- id
- f2b7a711-9f3a-40fd-a891-379e80e49c7f
- date added to LUP
- 2023-08-23 12:57:56
- date last changed
- 2024-04-20 01:21:08
@article{f2b7a711-9f3a-40fd-a891-379e80e49c7f, abstract = {{<p>Reactive oxygen species (ROS) are implicated in epithelial cell-state transition and deposition of extracellular matrix upon airway injury. Of the many cellular targets of ROS, oxidative DNA modification is a major driving signal. However, the role of oxidative DNA damage in modulation profibrotic processes has not been fully delineated. Herein, we report that oxidative DNA base lesions, 8-oxoG, complexed with 8-oxoguanine DNA glycosylase 1 (OGG1) functions as a pioneer factor, contributing to transcriptional reprogramming within airway epithelial cells. We show that TGFβ1-induced ROS increased 8-oxoG levels in open chromatin, dynamically reconfigure the chromatin state. OGG1 complexed with 8-oxoG recruits transcription factors, including phosphorylated SMAD3, to pro-fibrotic gene promoters thereby facilitating gene activation. Moreover, 8-oxoG levels are elevated in lungs of mice subjected to TGFβ1-induced injury. Pharmacologic targeting of OGG1 with the selective small molecule inhibitor of 8-oxoG binding, TH5487, abrogates fibrotic gene expression and remodeling in this model. Collectively, our study implicates that 8-oxoG substrate-specific binding by OGG1 is a central modulator of transcriptional regulation in response to tissue repair.</p>}}, author = {{Pan, Lang and Hao, Wenjing and Xue, Yaoyao and Wang, Ke and Zheng, Xu and Luo, Jixian and Ba, Xueqing and Xiang, Yang and Qin, Xiaoqun and Bergwik, Jesper and Tanner, Lloyd and Egesten, Arne and Brasier, Allan R. and Boldogh, Istvan}}, issn = {{0305-1048}}, language = {{eng}}, month = {{02}}, number = {{3}}, pages = {{1087--1102}}, publisher = {{Oxford University Press}}, series = {{Nucleic Acids Research}}, title = {{8-Oxoguanine targeted by 8-oxoguanine DNA glycosylase 1 (OGG1) is central to fibrogenic gene activation upon lung injury}}, url = {{http://dx.doi.org/10.1093/nar/gkac1241}}, doi = {{10.1093/nar/gkac1241}}, volume = {{51}}, year = {{2023}}, }