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DNA methylome alterations are associated with airway macrophage differentiation and phenotype during lung fibrosis.

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McErlean et al 2021_Accepted manuscript .pdfAccepted version4.52 MBAdobe PDFView/Open
Title: DNA methylome alterations are associated with airway macrophage differentiation and phenotype during lung fibrosis.
Authors: McErlean, P
Bell, CG
Hewitt, RJ
Busharat, Z
Ogger, PP
Ghai, P
Albers, GJ
Calamita, E
Kingston, S
Molyneaux, PL
Beck, S
Lloyd, CM
Maher, TM
Byrne, AJ
Item Type: Journal Article
Abstract: Rationale: Airway macrophages (AMs) are key regulators of the lung environment and are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a fatal respiratory disease with no cure. However, knowledge about the epigenetics of AMs in IPF is limited. Objectives: To assess the role of epigenetic regulation of AMs during lung fibrosis. Methods: We undertook DNA methylation (DNAm) profiling by using Illumina EPIC (850k) arrays in sorted AMs from healthy donors (n = 14) and donors with IPF (n = 30). Cell-type deconvolution was performed by using reference myeloid-cell DNA methylomes. Measurements and Main Results: Our analysis revealed that epigenetic heterogeneity was a key characteristic of IPF AMs. DNAm "clock" analysis indicated that epigenetic alterations in IPF AMs were not associated with accelerated aging. In differential DNAm analysis, we identified numerous differentially methylated positions (n = 11) and differentially methylated regions (n = 49) between healthy and IPF AMs, respectively. Differentially methylated positions and differentially methylated regions encompassed genes involved in lipid (LPCAT1 [lysophosphatidylcholine acyltransferase 1]) and glucose (PFKFB3 [6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3]) metabolism, and importantly, the DNAm status was associated with disease severity in IPF. Conclusions: Collectively, our data identify that changes in the epigenome are associated with the development and function of AMs in the IPF lung.
Issue Date: 15-Oct-2021
Date of Acceptance: 19-Jul-2021
URI: http://hdl.handle.net/10044/1/92349
DOI: 10.1164/rccm.202101-0004OC
ISSN: 1073-449X
Publisher: American Thoracic Society
Start Page: 954
End Page: 966
Journal / Book Title: American Journal of Respiratory and Critical Care Medicine
Volume: 204
Issue: 8
Copyright Statement: © 2021 by the American Thoracic Society
Sponsor/Funder: Action for Pulmonary Fibrosis
Funder's Grant Number: n/a
Keywords: DNA methylation
epigenetics
interstitial lung disease
monocytes
pathogenesis
DNA methylation
epigenetics
interstitial lung disease
monocytes
pathogenesis
11 Medical and Health Sciences
Respiratory System
Publication Status: Published
Conference Place: United States
Online Publication Date: 2021-10-15
Appears in Collections:National Heart and Lung Institute