Epigenetics in health and disease : on smoking, multiple sclerosis, and rheumatoid arthritis disease states
Author: Ringh, Mikael
Date: 2019-10-25
Location: Lilla Salen, Astrid Lindgrens Barnsjukhus Q-huset (QA31:01), Karolinska Universitetssjukhuset, Solna
Time: 09.00
Department: Inst för klinisk neurovetenskap / Dept of Clinical Neuroscience
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Thesis (578.3Kb)
Abstract
The main aim of this thesis was to investigate the genome-wide DNA methylation in tissues associated with the immunopathogenesis of two autoimmune diseases, Rheumatoid Arthritis (RA) and Multiple Sclerosis (MS), as well as smoking-associated methylome patterns in the lung.
In Study I, we investigated the methylome of two sets of monozygotic twin pairs, representing two phases of anti citrulline protein antibody (ACPA)-positive RA disease development. The first set included five MZ twin pairs discordant for APCA at risk for developing RA, and the second set included seven pairs discordant for ACPA-positive RA. A differentially methylated region associated with a protocadherin (PCDH) gene proposes a temporal epigenetic connection in the progression from ACPA-positivity to clinical RA. In Study II, we investigated the impact of tobacco smoking on bronchoalveolar lavage (BAL), which mainly consists of tissue-resident alveolar macrophages. We combined methylome and transcriptome data from BAL cells from healthy individuals and provide novel smoking-associated signatures converging to genes involved in migration, signaling and inflammatory response of immune cells. Of note, many of the sites in the smoking-associated methylome signature map to enhancer regions. Our findings propose that the epigenetic landscape of BAL cells is modified in smokers, and that it may involve active demethylation resulting in induced immune-related activities in the lung. Despite strong evidence that cigarette smoking is a risk factor for MS, little research has focused on smoking-associated changes in the lung of MS patients. In Study III, we show that smoking in MS patients resulted in subtle alterations in their methylome related to neuronal processes. Additionally, non-smoking MS patients displayed very discrete changes in transcriptional and translational processes and enhanced cellular motility, supporting findings on lung involvement in the pathogenesis of MS-like disease in animal studies.
In conclusion, we demonstrate a non-genetically linked temporal epigenetic connection between ACPA-positivity and clinical RA that may be of interest in future studies. We reveal smoking-associated changes in the epigenetic landscape of BAL cells, and increased activity of immune-related processes in the lung, possibly involving active demethylation. We also present new insights into the impact of cigarette smoking on pulmonary inflammation in the immunopathogenesis of MS.
In Study I, we investigated the methylome of two sets of monozygotic twin pairs, representing two phases of anti citrulline protein antibody (ACPA)-positive RA disease development. The first set included five MZ twin pairs discordant for APCA at risk for developing RA, and the second set included seven pairs discordant for ACPA-positive RA. A differentially methylated region associated with a protocadherin (PCDH) gene proposes a temporal epigenetic connection in the progression from ACPA-positivity to clinical RA. In Study II, we investigated the impact of tobacco smoking on bronchoalveolar lavage (BAL), which mainly consists of tissue-resident alveolar macrophages. We combined methylome and transcriptome data from BAL cells from healthy individuals and provide novel smoking-associated signatures converging to genes involved in migration, signaling and inflammatory response of immune cells. Of note, many of the sites in the smoking-associated methylome signature map to enhancer regions. Our findings propose that the epigenetic landscape of BAL cells is modified in smokers, and that it may involve active demethylation resulting in induced immune-related activities in the lung. Despite strong evidence that cigarette smoking is a risk factor for MS, little research has focused on smoking-associated changes in the lung of MS patients. In Study III, we show that smoking in MS patients resulted in subtle alterations in their methylome related to neuronal processes. Additionally, non-smoking MS patients displayed very discrete changes in transcriptional and translational processes and enhanced cellular motility, supporting findings on lung involvement in the pathogenesis of MS-like disease in animal studies.
In conclusion, we demonstrate a non-genetically linked temporal epigenetic connection between ACPA-positivity and clinical RA that may be of interest in future studies. We reveal smoking-associated changes in the epigenetic landscape of BAL cells, and increased activity of immune-related processes in the lung, possibly involving active demethylation. We also present new insights into the impact of cigarette smoking on pulmonary inflammation in the immunopathogenesis of MS.
List of papers:
I. Gomez-Cabrero D*, Almgren M*, Sjöholm LK*, Hensvold AH*, Ringh MV, Tryggvadottir R, Kere J, Scheynius A, Acevedo N, Reinius L, Taub MA, Montano C, Aryee MJ, Feinberg J, Feinberg AP, Tegnér J, Klareskog L, Catrina AI, Ekström TJ. High-specificity bioinformatics framework for epigenomic profiling of discordant twins reveals specific and shared markers for ACPA and ACPA-positive rheumatoid arthritis. Genome Med. 2016 Nov 22;8(1):124. *These authors contributed equally.
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II. Ringh MV, Hagemann-Jensen M, Needhamsen M, Kular L, Breeze CE, Sjöholm LK, Slavec L, Kullberg S, Wahlström J, Grunewald J, Brynedal B, Liu Y, Almgren M, Jagodic M, Öckinger J, Ekström TJ. Tobacco smoking induces changes in true DNA methylation, hydroxymethylation and gene expression in bronchoalveolar lavage cells. EBioMedicine. 2019 Aug;46:290-304.
Fulltext (DOI)
Pubmed
III. Ringh MV*, Hagemann-Jensen M*, Needhamsen M, Kullberg S, Wahlström J, Grunewald J, Brynedal B, Jagodic M, Ekström TJ, Öckinger J, Kular L. Methylome and transcriptome signature of bronchoalveolar cells from Multiple Sclerosis patients. *These authors contributed equally. [Manuscript]
I. Gomez-Cabrero D*, Almgren M*, Sjöholm LK*, Hensvold AH*, Ringh MV, Tryggvadottir R, Kere J, Scheynius A, Acevedo N, Reinius L, Taub MA, Montano C, Aryee MJ, Feinberg J, Feinberg AP, Tegnér J, Klareskog L, Catrina AI, Ekström TJ. High-specificity bioinformatics framework for epigenomic profiling of discordant twins reveals specific and shared markers for ACPA and ACPA-positive rheumatoid arthritis. Genome Med. 2016 Nov 22;8(1):124. *These authors contributed equally.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Ringh MV, Hagemann-Jensen M, Needhamsen M, Kular L, Breeze CE, Sjöholm LK, Slavec L, Kullberg S, Wahlström J, Grunewald J, Brynedal B, Liu Y, Almgren M, Jagodic M, Öckinger J, Ekström TJ. Tobacco smoking induces changes in true DNA methylation, hydroxymethylation and gene expression in bronchoalveolar lavage cells. EBioMedicine. 2019 Aug;46:290-304.
Fulltext (DOI)
Pubmed
III. Ringh MV*, Hagemann-Jensen M*, Needhamsen M, Kullberg S, Wahlström J, Grunewald J, Brynedal B, Jagodic M, Ekström TJ, Öckinger J, Kular L. Methylome and transcriptome signature of bronchoalveolar cells from Multiple Sclerosis patients. *These authors contributed equally. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Ekström, Tomas
Co-supervisor: Almgren, Malin; Catrina, Anca; Vähämaa, Heidi; Liu, Yun
Issue date: 2019-10-03
Rights:
Publication year: 2019
ISBN: 978-91-7831-581-9
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