RT Journal Article
SR Electronic
T1 Epigenetic alterations underlie airway macrophage differentiation and phenotype during lung fibrosis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.12.04.410191
DO 10.1101/2020.12.04.410191
A1 Peter McErlean
A1 Christopher G. Bell
A1 Richard J. Hewitt
A1 Zabreen Busharat
A1 Patricia P. Ogger
A1 Poonam Ghai
A1 Gesa Albers
A1 Shaun Kingston
A1 Philip L. Molyneaux
A1 Stephan Beck
A1 Clare M. Lloyd
A1 Toby M. Maher
A1 Adam J Byrne
YR 2020
UL http://biorxiv.org/content/early/2020/12/04/2020.12.04.410191.abstract
AB 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, the epigenetics of AMs development and function in IPF are limited. Here, we characterised the DNA-methylation (DNAm) profile of AMs from IPF (n=30) and healthy (n=14) donors. Our analysis revealed epigenetic heterogeneity was a key characteristic of IPF AMs. DNAm ‘clock’ analysis indicated epigenetic alterations in IPF-AMs was not associated with accelerated ageing. In differential DNAm analysis, we identified numerous differentially methylated positions (DMPs, n=11) and regions (DMRs, n=49) between healthy and IPF AMs respectively. DMPs and DMRs encompassed genes involved in lipid (LPCAT1) and glucose (PFKB3) metabolism and importantly, DNAm status was associated with disease severity in IPF. Collectively, our data identify that profound changes in the epigenome underpin the development and function of AMs in the IPF lung.Competing Interest StatementA.J.B. received, unrelated to this work, consultancy fees from Ammax, Devpro, and Ionis pharmaceuticals, via his institution. Unrelated to the current work, T.M.M. has, via his institution, received industry- academic funding from GlaxoSmithKline R&D and UCB and has received consultancy or speakers fees from Apellis, Astra Zeneca, Bayer, Blade Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Galapagos, GlaxoSmithKline R&D, Indalo, Novartis, Pliant, ProMetic, Respivnat, Roche, Samumed, and UCB. P.L.M. received industry-academic funding from AstraZeneca and has received speaker and consultancy fees from Boehringer Ingelheim and Hoffman La Roche outside the submitted work via his institution.AbbreviationsAMsAirway macrophagesCpGCytosine-guanine dinucleotidesFVCForced vital capacityHCHealthy controlDHSDNase-I hypersensitivity sitesDNAmDNA methylationDMPsDifferentially methylated positionsDMRsDifferentially methylated regionsIPFIdiopathic pulmonary fibrosisMyld-CpGsMyeloid marker CpG dinucleotidespcHiCPromoter capture HiCscRNA-SeqSingle-cell RNA sequencingWGBSWhole genome bisulphite sequencing