Research Paper Volume 13, Issue 2 pp 1742—1764
DNA methylation perturbations may link altered development and aging in the lung
- 1 Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
- 2 Children's Mercy Hospital and Clinics, Kansas City, MO 64108, USA
- 3 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
Received: September 2, 2020 Accepted: December 18, 2020 Published: January 19, 2021
https://doi.org/10.18632/aging.202544How to Cite
Copyright: © 2021 Kachroo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Fetal perturbations in DNA methylation during lung development may reveal insights into the enduring impacts on adult lung health and disease during aging that have not been explored altogether before.
We studied the association between genome-wide DNA-methylation and post-conception age in fetal-lung (n=78, 42 exposed to in-utero-smoke (IUS)) tissue and chronological age in adult-lung tissue (n=160, 114 with Chronic Obstructive Pulmonary Disease) using multi-variate linear regression models with covariate adjustment and tested for effect modification by phenotypes. Overlapping age-associations were evaluated for functional and tissue-specific enrichment using the Genotype-Tissue-Expression (GTEx) project.
We identified 244 age-associated differentially methylated positions and 878 regions overlapping between fetal and adult-lung tissues. Hyper-methylated CpGs (96%) were enriched in transcription factor activity (FDR adjusted P=2x10-33) and implicated in developmental processes including embryonic organ morphogenesis, neurogenesis and growth delay. Hypo-methylated CpGs (2%) were enriched in oxido-reductase activity and VEGFA-VEGFR2 Signaling. Twenty-one age-by-sex and eleven age-by-pack-years interactions were statistically significant (FDR<0.05) in adult-lung tissue.
DNA methylation in transcription factors during development in fetal lung recapitulates in adult-lung tissue with aging. These findings reveal molecular mechanisms and pathways that may link disrupted development in early-life and age-associated lung diseases.
Abbreviations
IUS: in-utero-smoke; COPD: Chronic Obstructive Pulmonary Disease; GTEx: Genotype-Tissue-Expression Project; UCSC: The University of California Santa Cruz; CHR: chromosome; FDR: false discovery rate; P: P-value; DNA: Deoxyribonucleic acid; RNA: Ribonucleic acid; ALT: adult lung tissue; LAA-950: fraction of lung voxels with low attenuation areas at less than -950 Hounsfield Units; aDMPs: age-associated differentially methylated positions; DMRs: differentially methylated regions; TRACE: fasT and Robust Ancestry Coordinate Estimation; PCs: principal components; sva: surrogate variable analysis; GREAT: Genomic Regions Enrichment of Annotations Tool; DNAmAge: DNA methylation age; EWAS: epigenome-wide association study; mQTLs: methylation quantitative trait loci; SNORA/snoRNAs: small nucleolar RNAs; scaRNAs/SCARNA: small cajal body-specific RNAs; MSigDB: The Molecular Signatures Database; IPF: idiopathic pulmonary fibrosis; VEGFA-VEGFR2: Vascular Endothelial Growth Factor A-Vascular endothelial growth factor receptor 2.