Integrated analysis of ATAC-seq and RNA-seq unveils the role of ferroptosis in PM2.5-induced asthma exacerbation

作者全名："Zhang, Yi; Jiang, Manling; Xiong, Ying; Zhang, Lei; Xiong, Anying; Wang, Junyi; He, Xiang; Li, Guoping"

作者地址："[Zhang, Yi; Jiang, Manling; Zhang, Lei; Xiong, Anying; Wang, Junyi; He, Xiang; Li, Guoping] Southwest Jiaotong Univ, Peoples Hosp Chengdu 3, Chengdu Inst Resp Hlth, Sch Med,Lab Allergy & Precis Med,Affiliated Hosp, Chengdu 610031, Peoples R China; [Zhang, Yi; Jiang, Manling; Zhang, Lei; Xiong, Anying; Wang, Junyi; He, Xiang; Li, Guoping] ChongQing Med Univ, Natl Clin Res Ctr Resp Dis, Affiliated Hos, Dept Pulm & Crit Care Med,Chengdu Peoples Hosp Bra, Chengdu 610031, Peoples R China; [Xiong, Ying] Sichuan Friendship Hosp, Dept Pulm & Crit Care Med, Chengdu 610000, Peoples R China"

通信作者："He, X; Li, GP (通讯作者)，Southwest Jiaotong Univ, Peoples Hosp Chengdu 3, Chengdu Inst Resp Hlth, Sch Med,Lab Allergy & Precis Med,Affiliated Hosp, Chengdu 610031, Peoples R China."

来源：INTERNATIONAL IMMUNOPHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001117332000001

JCR分区：Q1

影响因子：4.8

年份：2023

卷号：125

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：PM2.5; Epigenetic modifications; Ferroptosis; Asthma; FTH1; FTL

摘要："Background: PM2.5 exposure increases asthma exacerbation risk and worsens airway inflammation and mucus secretion, but the underlying mechanisms, especially the epigenetic modification changes, are not fully understood. Methods: ATAC-seq was conducted in Beas-2B cells to explore the differential chromatin accessibilities before and after exposure to PM2.5. RNA-seq was applied to screen the differentially expressed genes (DEGs) as well. The integrated analysis of ATAC-seq and RNA-seq was performed. The key up-regulated genes in the ferroptosis signaling pathway were identified by combined analysis with the FerrDb database and then verified. Meanwhile, to access the role of PM2.5-induced ferroptosis in asthma mice, house dust mites (HDM) were employed to conduct an allergic asthma mice model, and the ferroptosis-specific inhibitor (Ferrostatin-1, Fer-1) was used. The H&E staining, PAS staining, airway hyperresponsiveness, and bronchoalveolar lavage fluid (BALF) cell counting were used to investigate the impact of PM2.5-induced ferroptosis in asthma mice. Results: A total of 4,921 regions with differential accessibility were identified, encompassing 4,031 unique genes. Among these, 250 regions exhibited increased accessibility while 4,671 regions displayed reduced accessibility. Through the integrated analysis of ATAC-seq and RNA-seq, ferroptosis was determined as the key enriched pathway based on up-regulated DEGs and increased chromatin accessibilities. Furthermore, the decreased cell viability, accelerated lipid peroxide and morphological changes in mitochondria observed upon PM2.5 exposure were rescued by Fer-1, which are indicative of ferroptosis. By overlapping with ferroptosis-related genes from the FerrDb database, FTH1 and FTL were identified as the prominent up-regulated genes with increased chromatin accessibility in ferroptosis pathway. In addition, ChIP-qPCR analysis indicated that histone modification like H3K4me3 and H3K27ac positively regulated FTH1 and FTL expression. Subsequently, in PM2.5-exposed asthmatic mice, inhibition of ferroptosis effectively attenuated airway inflammation and mucus secretion. Conclusion: These findings shed light on the molecular mechanisms underlying PM2.5-induced asthma exacerbation, with epigenetic modifications playing a pivotal role. Furthermore, it suggests the therapeutic potential of targeting ferroptosis as an intervention strategy."

基金机构："National Natural Science Foundation of China [82370023, 82370022]; China Postdoctoral Science Foundation [2023M730799]; Chengdu High-level Key Clinical Specialty Construction Project [ZX20201202020]; Chengdu Science and Technology Bureau [2021-YF09-00102-SN]; Health Commission of Chengdu [2021040, 2022193]; Sichuan medical association [Q20009]; Sichuan provincial administration of traditional Chinese medicine [2020JC0118, 2020LC0212]"

基金资助正文："This work was supported by the National Natural Science Founda-tion of China (82370023, 82370022) , China Postdoctoral Science Foundation (2023M730799) , Chengdu High-level Key Clinical Specialty Construction Project (ZX20201202020) , Chengdu Science and Technology Bureau (2021-YF09-00102-SN) , Health Commission of Chengdu (2021040, 2022193) , Sichuan medical association (Q20009) , Sichuan provincial administration of traditional Chinese medicine (2020JC0118, 2020LC0212) ."