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Genome-wide DNA methylation profiling shows a distinct epigenetic signature associated with lung macrophages in cystic fibrosis
BACKGROUND: Lung macrophages are major participants in the pulmonary innate immune response. In the cystic fibrosis (CF) lung, the inability of lung macrophages to successfully regulate the exaggerated inflammatory response suggests dysfunctional innate immune cell function. In this study, we aim to...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288922/ https://www.ncbi.nlm.nih.gov/pubmed/30526669 http://dx.doi.org/10.1186/s13148-018-0580-2 |
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author | Chen, Youdinghuan Armstrong, David A. Salas, Lucas A. Hazlett, Haley F. Nymon, Amanda B. Dessaint, John A. Aridgides, Daniel S. Mellinger, Diane L. Liu, Xiaoying Christensen, Brock C. Ashare, Alix |
author_facet | Chen, Youdinghuan Armstrong, David A. Salas, Lucas A. Hazlett, Haley F. Nymon, Amanda B. Dessaint, John A. Aridgides, Daniel S. Mellinger, Diane L. Liu, Xiaoying Christensen, Brock C. Ashare, Alix |
author_sort | Chen, Youdinghuan |
collection | PubMed |
description | BACKGROUND: Lung macrophages are major participants in the pulmonary innate immune response. In the cystic fibrosis (CF) lung, the inability of lung macrophages to successfully regulate the exaggerated inflammatory response suggests dysfunctional innate immune cell function. In this study, we aim to gain insight into innate immune cell dysfunction in CF by investigating alterations in DNA methylation in bronchoalveolar lavage (BAL) cells, composed primarily of lung macrophages of CF subjects compared with healthy controls. All analyses were performed using primary alveolar macrophages from human subjects collected via bronchoalveolar lavage. Epigenome-wide DNA methylation was examined via Illumina MethylationEPIC (850 K) array. Targeted next-generation bisulfite sequencing was used to validate selected differentially methylated CpGs. Methylation-based sample classification was performed using the recursively partitioned mixture model (RPMM) and was tested against sample case-control status. Differentially methylated loci were identified by fitting linear models with adjustment of age, sex, estimated cell type proportions, and repeat measurement. RESULTS: RPMM class membership was significantly associated with the CF disease status (P = 0.026). One hundred nine CpG loci were differentially methylated in CF BAL cells (all FDR ≤ 0.1). The majority of differentially methylated loci in CF were hypo-methylated and found within non-promoter CpG islands as well as in putative enhancer regions and DNase hyper-sensitive regions. CONCLUSIONS: These results support a hypothesis that epigenetic changes, specifically DNA methylation at a multitude of gene loci in lung macrophages, may participate, at least in part, in driving dysfunctional innate immune cells in the CF lung. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13148-018-0580-2) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6288922 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-62889222018-12-14 Genome-wide DNA methylation profiling shows a distinct epigenetic signature associated with lung macrophages in cystic fibrosis Chen, Youdinghuan Armstrong, David A. Salas, Lucas A. Hazlett, Haley F. Nymon, Amanda B. Dessaint, John A. Aridgides, Daniel S. Mellinger, Diane L. Liu, Xiaoying Christensen, Brock C. Ashare, Alix Clin Epigenetics Research BACKGROUND: Lung macrophages are major participants in the pulmonary innate immune response. In the cystic fibrosis (CF) lung, the inability of lung macrophages to successfully regulate the exaggerated inflammatory response suggests dysfunctional innate immune cell function. In this study, we aim to gain insight into innate immune cell dysfunction in CF by investigating alterations in DNA methylation in bronchoalveolar lavage (BAL) cells, composed primarily of lung macrophages of CF subjects compared with healthy controls. All analyses were performed using primary alveolar macrophages from human subjects collected via bronchoalveolar lavage. Epigenome-wide DNA methylation was examined via Illumina MethylationEPIC (850 K) array. Targeted next-generation bisulfite sequencing was used to validate selected differentially methylated CpGs. Methylation-based sample classification was performed using the recursively partitioned mixture model (RPMM) and was tested against sample case-control status. Differentially methylated loci were identified by fitting linear models with adjustment of age, sex, estimated cell type proportions, and repeat measurement. RESULTS: RPMM class membership was significantly associated with the CF disease status (P = 0.026). One hundred nine CpG loci were differentially methylated in CF BAL cells (all FDR ≤ 0.1). The majority of differentially methylated loci in CF were hypo-methylated and found within non-promoter CpG islands as well as in putative enhancer regions and DNase hyper-sensitive regions. CONCLUSIONS: These results support a hypothesis that epigenetic changes, specifically DNA methylation at a multitude of gene loci in lung macrophages, may participate, at least in part, in driving dysfunctional innate immune cells in the CF lung. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13148-018-0580-2) contains supplementary material, which is available to authorized users. BioMed Central 2018-12-10 /pmc/articles/PMC6288922/ /pubmed/30526669 http://dx.doi.org/10.1186/s13148-018-0580-2 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Chen, Youdinghuan Armstrong, David A. Salas, Lucas A. Hazlett, Haley F. Nymon, Amanda B. Dessaint, John A. Aridgides, Daniel S. Mellinger, Diane L. Liu, Xiaoying Christensen, Brock C. Ashare, Alix Genome-wide DNA methylation profiling shows a distinct epigenetic signature associated with lung macrophages in cystic fibrosis |
title | Genome-wide DNA methylation profiling shows a distinct epigenetic signature associated with lung macrophages in cystic fibrosis |
title_full | Genome-wide DNA methylation profiling shows a distinct epigenetic signature associated with lung macrophages in cystic fibrosis |
title_fullStr | Genome-wide DNA methylation profiling shows a distinct epigenetic signature associated with lung macrophages in cystic fibrosis |
title_full_unstemmed | Genome-wide DNA methylation profiling shows a distinct epigenetic signature associated with lung macrophages in cystic fibrosis |
title_short | Genome-wide DNA methylation profiling shows a distinct epigenetic signature associated with lung macrophages in cystic fibrosis |
title_sort | genome-wide dna methylation profiling shows a distinct epigenetic signature associated with lung macrophages in cystic fibrosis |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288922/ https://www.ncbi.nlm.nih.gov/pubmed/30526669 http://dx.doi.org/10.1186/s13148-018-0580-2 |
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