Epigenomic response to albuterol treatment in asthma-relevant airway epithelial cells

Clinical Epigenetics

Research

Jesús Villar¹  Elizabeth G. Plender²  Nathan D. Jackson²  Jamie L. Everman²  Camille M. Moore³  Max A. Seibold⁴  José Rodríguez-Santana⁵  Vivian Medina⁵  Celeste Eng⁶  Esteban G. Burchard⁷  Daniel Efrain Winnica⁸  Fernando Holguin⁸  Sunita Sharma⁸  Javier Perez-Garcia⁹  Maria Pino-Yanes^1,10  Elad Ziv^1,11  Kenneth B. Beckman^1,12 

[1] CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain;Multidisciplinary Organ Dysfunction Evaluation Research Network (MODERN), Research Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain;Li Ka Shing Knowledge Institute at the St. Michael’s Hospital, Toronto, ON, Canada;Center for Genes, Environment, and Health, National Jewish Health, Denver, CO, USA;Center for Genes, Environment, and Health, National Jewish Health, Denver, CO, USA;Department of Biomedical Research, National Jewish Health, Denver, CO, USA;Department of Biostatistics and Informatics, University of Colorado, Denver, CO, USA;Center for Genes, Environment, and Health, National Jewish Health, Denver, CO, USA;Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA;Department of Pediatrics, National Jewish Health, Denver, CO, USA;Centro de Neumología Pediátrica, San Juan, PR, USA;Department of Medicine, University of California San Francisco (UCSF), San Francisco, CA, USA;Department of Medicine, University of California San Francisco (UCSF), San Francisco, CA, USA;Department of Bioengineering and Therapeutic Sciences, University of California San Francisco (UCSF), San Francisco, CA, USA;Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, USA;Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology, and Genetics, Universidad de La Laguna (ULL), La Laguna, Tenerife, Canary Islands, Spain;Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology, and Genetics, Universidad de La Laguna (ULL), La Laguna, Tenerife, Canary Islands, Spain;CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain;Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna (ULL), La Laguna, Spain;Institute for Human Genetics, University of California San Francisco (UCSF), San Francisco, CA, USA;Department of Epidemiology and Biostatistics, University of California, San Francisco School of Medicine, San Francisco, CA, USA;University of Minnesota Genomics Center (UMNGC), Minneapolis, MN, USA;

关键词: Airway cells;    Albuterol;    β-agonist;    CREB3L1;    DNA methylation;    Epigenetics;    EWAS;    KSR1;    MYLK4;    Puerto Ricans;   

DOI  :  10.1186/s13148-023-01571-0

 received in 2023-03-02, accepted in 2023-09-25,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundAlbuterol is the first-line asthma medication used in diverse populations. Although DNA methylation (DNAm) is an epigenetic mechanism involved in asthma and bronchodilator drug response (BDR), no study has assessed whether albuterol could induce changes in the airway epithelial methylome. We aimed to characterize albuterol-induced DNAm changes in airway epithelial cells, and assess potential functional consequences and the influence of genetic variation and asthma-related clinical variables.ResultsWe followed a discovery and validation study design to characterize albuterol-induced DNAm changes in paired airway epithelial cultures stimulated in vitro with albuterol. In the discovery phase, an epigenome-wide association study using paired nasal epithelial cultures from Puerto Rican children (n = 97) identified 22 CpGs genome-wide associated with repeated-use albuterol treatment (p < 9 × 10–8). Albuterol predominantly induced a hypomethylation effect on CpGs captured by the EPIC array across the genome (probability of hypomethylation: 76%, p value = 3.3 × 10–5). DNAm changes on the CpGs cg23032799 (CREB3L1), cg00483640 (MYLK4-LINC01600), and cg05673431 (KSR1) were validated in nasal epithelia from 10 independent donors (false discovery rate [FDR] < 0.05). The effect on the CpG cg23032799 (CREB3L1) was cross-tissue validated in bronchial epithelial cells at nominal level (p = 0.030). DNAm changes in these three CpGs were shown to be influenced by three independent genetic variants (FDR < 0.05). In silico analyses showed these polymorphisms regulated gene expression of nearby genes in lungs and/or fibroblasts including KSR1 and LINC01600 (6.30 × 10–14 ≤ p ≤ 6.60 × 10–5). Additionally, hypomethylation at the CpGs cg10290200 (FLNC) and cg05673431 (KSR1) was associated with increased gene expression of the genes where they are located (FDR < 0.05). Furthermore, while the epigenetic effect of albuterol was independent of the asthma status, severity, and use of medication, BDR was nominally associated with the effect on the CpG cg23032799 (CREB3L1) (p = 0.004). Gene-set enrichment analyses revealed that epigenomic modifications of albuterol could participate in asthma-relevant processes (e.g., IL-2, TNF-α, and NF-κB signaling pathways). Finally, nine differentially methylated regions were associated with albuterol treatment, including CREB3L1, MYLK4, and KSR1 (adjusted p value < 0.05).ConclusionsThis study revealed evidence of epigenetic modifications induced by albuterol in the mucociliary airway epithelium. The epigenomic response induced by albuterol might have potential clinical implications by affecting biological pathways relevant to asthma.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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