Abstract

Epigenetic changes are required for normal development, yet the nature and respective contribution of factors that drive epigenetic variation in humans remain to be fully characterized. Here, we assessed how the blood DNA methylome of 884 adults is affected by DNA sequence variation, age, sex and 139 factors relating to life habits and immunity. Furthermore, we investigated whether these effects are mediated or not by changes in cellular composition, measured by deep immunophenotyping. We show that DNA methylation differs substantially between naïve and memory T cells, supporting the need for adjustment on these cell-types. By doing so, we find that latent cytomegalovirus infection drives DNA methylation variation and provide further support that the increased dispersion of DNA methylation with aging is due to epigenetic drift. Finally, our results indicate that cellular composition and DNA sequence variation are the strongest predictors of DNA methylation, highlighting critical factors for medical epigenomics studies.

Many studies assess epigenetic marks in white blood cells, but it is unclear how much immune factors affect the epigenome. Here, the authors show that fine-scale blood cell composition and cytomegalovirus infection affect the DNA methylome of adults.

Details

Title
The immune factors driving DNA methylation variation in human blood
Author
Bergstedt, Jacob 1   VIAFID ORCID Logo  ; Azzou, Sadoune Ait Kaci 2   VIAFID ORCID Logo  ; Tsuo, Kristin 2   VIAFID ORCID Logo  ; Jaquaniello, Anthony 2 ; Urrutia, Alejandra 3 ; Rotival, Maxime 2   VIAFID ORCID Logo  ; Lin, David T. S. 4 ; MacIsaac, Julia L. 4 ; Kobor, Michael S. 4   VIAFID ORCID Logo  ; Albert, Matthew L. 5   VIAFID ORCID Logo  ; Duffy, Darragh 6   VIAFID ORCID Logo  ; Patin, Etienne 2   VIAFID ORCID Logo  ; Quintana-Murci, Lluís 7   VIAFID ORCID Logo  ; Abel, Laurent 8 ; Alcover, Andres 9 ; Aschard, Hugues 10 ; Bousso, Philippe 11 ; Bourke, Nollaig 12 ; Brodin, Petter 13 ; Bruhns, Pierre 14 ; Cerf-Bensussan, Nadine 15 ; Cumano, Ana 16 ; d’Enfert, Christophe 11 ; Deriano, Ludovic 17 ; Dillies, Marie-Agnès 18 ; Di Santo, James 19 ; Dromer, Françoise 20 ; Eberl, Gérard 21 ; Enninga, Jost 22 ; Fellay, Jacques 23 ; Gomperts-Boneca, Ivo 24 ; Hasan, Milena 25 ; Hedestam, Gunilla Karlsson 26 ; Hercberg, Serge 27 ; Ingersoll, Molly A. 28 ; Lantz, Olivier 29 ; Kenny, Rose Anne 30 ; Ménager, Mickaël 31 ; Michel, Frédérique 32 ; Mouquet, Hugo 33 ; O’Farrelly, Cliona 34 ; Pellegrini, Sandra 32 ; Rausell, Antonio 35 ; Rieux-Laucat, Frédéric 36 ; Rogge, Lars 37 ; Fontes, Magnus 38 ; Sakuntabhai, Anavaj 39 ; Schwartz, Olivier 40 ; Schwikowski, Benno 41 ; Shorte, Spencer 42 ; Tangy, Frédéric 43 ; Toubert, Antoine 44 ; Touvier, Mathilde 27 ; Ungeheuer, Marie-Noëlle 45 ; Zimmer, Christophe 46 ; Quintana-Murci, Lluis 7 

1  Human Evolutionary Genetics Unit, Institut Pasteur, Université Paris Cité, CNRS UMR2000, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535); Karolinska Institutet, Unit of Integrative Epidemiology, Institute of Environmental Medicine, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626); Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626) 
2  Human Evolutionary Genetics Unit, Institut Pasteur, Université Paris Cité, CNRS UMR2000, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535) 
3  HI-Bio, South San Francisco, USA (GRID:grid.428999.7) 
4  University of British Columbia, Edwin S.H. Leong Healthy Aging Program, Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830) 
5  HI-Bio, South San Francisco, USA (GRID:grid.17091.3e) 
6  Institut Pasteur, Université Paris Cité, Translational Immunology Unit, Institut Pasteur, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535) 
7  Human Evolutionary Genetics Unit, Institut Pasteur, Université Paris Cité, CNRS UMR2000, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535); Collège de France, Chair of Human Genomics and Evolution, Paris, France (GRID:grid.410533.0) (ISNI:0000 0001 2179 2236) 
8  Laboratory of Human Genetics of Infectious Diseases, Imagine Institute, University Paris Cité, Necker Hospital for Sick Children, INSERM UMR 1163, Paris, France (GRID:grid.412134.1) (ISNI:0000 0004 0593 9113) 
9  Ligue Nationale Contre le Cancer, Équipe Labellisée Ligue, Institut Pasteur, Université Paris Cité, INSERM-U1224, Unité Biologie Cellulaire des Lymphocytes, Paris, France (GRID:grid.452770.3) (ISNI:0000 0001 2226 6748) 
10  Institut Pasteur, Université Paris Cité, Department of Computational Biology, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535) 
11  Unité Biologie et Pathogénicité Fongiques, Institut Pasteur, Université Paris Cité, INRAE USC2019, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535) 
12  Trinity College Dublin, Department of Medical Gerontology, School of Medicine, Dublin, Ireland (GRID:grid.8217.c) (ISNI:0000 0004 1936 9705) 
13  Imperial College London, Department of Immunology and Inflammation, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111); Karolinska Institutet, Department of Women’s and Children’s Health, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626) 
14  Unit of Antibodies in Therapy and Pathology, Institut Pasteur, Université Paris Cité, INSERM UMR1222, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535) 
15  Laboratory Intestinal Immunity, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France (GRID:grid.462336.6) 
16  Unit Lymphocytes and Immunity, Institut Pasteur, Université Paris Cité, INSERM U1223, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535) 
17  Immunity and Cancer Unit, Institut Pasteur, Université Paris Cité, INSERM U1223, Équipe Labellisée Ligue Contre Le Cancer, Genome Integrity, Paris, France (GRID:grid.462340.7) (ISNI:0000 0004 1793 5478) 
18  Bioinformatics and Biostatistics Hub, Institut Pasteur, Université Paris Cité, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535) 
19  Innate Immunity Unit, Institut Pasteur, Université Paris Cité, INSERM U1223, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535) 
20  Centre national de Référence Mycoses Invasives et Antifongiques, Institut Pasteur, Université Paris Cité, CNRS UMR2000, Unité de Mycologie Moléculaire, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535) 
21  Microenvironment and Immunity Unit, Institut Pasteur, Université Paris Cité, INSERM U1224, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535) 
22  Dynamics of Host-Pathogen Interactions Unit, Institut Pasteur, Université Paris Cité, CNRS UMR3691, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535) 
23  École Polytechnique Fédérale de Lausanne, School of Life Sciences, Lausanne, Switzerland (GRID:grid.5333.6) (ISNI:0000000121839049); Swiss Institute of Bioinformatics, Lausanne, Switzerland (GRID:grid.419765.8) (ISNI:0000 0001 2223 3006); Lausanne University Hospital and University of Lausanne, Precision Medicine Unit, Lausanne, Switzerland (GRID:grid.8515.9) (ISNI:0000 0001 0423 4662) 
24  Unité Biologie et Génétique de la Paroi Bactérienne, Institut Pasteur, Université Paris Cité, CNRS UMR2001, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535) 
25  Cytometry and Biomarkers Unit of Technology and Service, Institut Pasteur, Université Paris Cité, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535) 
26  Karolinska Institutet, Department of Microbiology, Tumor and Cell Biology, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626) 
27  Nutritional Epidemiology Research Team, Université Sorbonne Paris Nord, Université de Paris, INSERM U1153, INRAE U1125, CNAM, Epidemiology and Statistics Research Center, Bobigny, France (GRID:grid.508487.6) (ISNI:0000 0004 7885 7602) 
28  Mucosal Inflammation and Immunity Group, Institut Pasteur, Université Paris Cité, Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris, France (GRID:grid.508487.6) 
29  Laboratoire d’Immunologie Clinique, Institut Curie, Université Paris Sciences et Lettres, INSERM U932, Paris, France (GRID:grid.418596.7) (ISNI:0000 0004 0639 6384); Centre d’Investigation Clinique en Biothérapie Gustave-Roussy Institut Curie (CIC-BT1428), Paris, France (GRID:grid.418596.7) (ISNI:0000 0004 0639 6384) 
30  Trinity College Dublin, The Irish Longitudinal Study on Ageing (TILDA), Dublin, Ireland (GRID:grid.8217.c) (ISNI:0000 0004 1936 9705); Mercer’s Institute for Successful Ageing, St James’s Hospital, Dublin, Ireland (GRID:grid.416409.e) (ISNI:0000 0004 0617 8280) 
31  Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, Imagine Institute, Université Paris Cité, INSERM UMR1163, Paris, France (GRID:grid.462336.6) 
32  Cytokine Signaling Unit, Institut Pasteur, Université Paris Cité, INSERM U1221, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535) 
33  Laboratory of Humoral Immunology, Institut Pasteur, Université Paris Cité, INSERM U1222, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535) 
34  Trinity Biomedical Sciences Institute, Comparative Immunology, School of Biochemistry and Immunology, Dublin, Ireland (GRID:grid.8217.c) (ISNI:0000 0004 1936 9705); Trinity College Dublin, School of Medicine, Dublin, Ireland (GRID:grid.8217.c) (ISNI:0000 0004 1936 9705) 
35  Clinical Bioinformatics Laboratory, Imagine Institute, Université Paris Cité, INSERM UMR1163, Necker Hospital for Sick Children, Paris, France (GRID:grid.412134.1) (ISNI:0000 0004 0593 9113) 
36  Laboratory of Immunogenetics of Autoimmune Diseases in Children, Imagine Institute, Université Paris Cité, INSERM UMR 1163, Paris, France (GRID:grid.462336.6) 
37  Université Paris Cité, AP-HP Hôpital Cochin, Immunoregulation Unit, Institut Pasteur, Paris, France (GRID:grid.411784.f) (ISNI:0000 0001 0274 3893) 
38  Institut Roche, Boulogne-Billancourt, France (GRID:grid.411784.f) 
39  Functional Genetics of Infectious Diseases Unit, Institut Pasteur, Université Paris Cité, CNRS UMR2000, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535) 
40  Virus and Immunity Unit, Institut Pasteur, Université Paris Cité, CNRS UMR3569, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535) 
41  Computational Systems Biomedicine Lab, Institut Pasteur, Université Paris Cité, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535) 
42  Université Paris Cité, UTechS-PBI/Imagopole, Institut Pasteur, Paris, France (GRID:grid.508487.6) (ISNI:0000 0004 7885 7602) 
43  Viral Genomics and Vaccination Unit, Institut Pasteur, Université Paris Cité, CNRS UMR3965, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535) 
44  Laboratoire d’Immunologie et d’Histocompatibilité, AP-HP, Hôpital Saint-Louis, Université de Paris, INSERM UMR1160, Paris, France (GRID:grid.428999.7) 
45  Université Paris Cité, Investigation Clinique et Accès aux Ressources Biologiques (ICAReB), Institut Pasteur, Paris, France (GRID:grid.508487.6) (ISNI:0000 0004 7885 7602) 
46  Imaging and Modeling Unit, Institut Pasteur, Université Paris Cité, CNRS UMR3691, Paris, France (GRID:grid.428999.7) (ISNI:0000 0001 2353 6535) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-022-33511-6
ProQuest document ID
2722021597
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.