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1. Epigenetic and transcriptomic reprogramming in monocytes of severe COVID-19 patients reflects alterations in myeloid differentiation and the influence of inflammatory cytokines

Author

Gerard Godoy-Tena, Anis Barmada, Octavio Morante-Palacios, Carlos de la Calle-Fabregat, Ricardo Martins-Ferreira, Anna G. Ferreté-Bonastre, Laura Ciudad, Adolfo Ruiz-Sanmartín, Mónica Martínez-Gallo, Ricard Ferrer, Juan Carlos Ruiz-Rodriguez, Javier Rodríguez-Ubreva, Roser Vento-Tormo, and Esteban Ballestar

Subjects
COVID-19, Monocytes, Epigenomics, DNA methylation, Single-cell transcriptomics, Immune cell crosstalk, Medicine, Genetics, QH426-470
Abstract

Abstract Background COVID-19 manifests with a wide spectrum of clinical phenotypes, ranging from asymptomatic and mild to severe and critical. Severe and critical COVID-19 patients are characterized by marked changes in the myeloid compartment, especially monocytes. However, little is known about the epigenetic alterations that occur in these cells during hyperinflammatory responses in severe COVID-19 patients. Methods In this study, we obtained the DNA methylome and transcriptome of peripheral blood monocytes from severe COVID-19 patients. DNA samples extracted from CD14 + CD15- monocytes of 48 severe COVID-19 patients and 11 healthy controls were hybridized on MethylationEPIC BeadChip arrays. In parallel, single-cell transcriptomics of 10 severe COVID-19 patients were generated. CellPhoneDB was used to infer changes in the crosstalk between monocytes and other immune cell types. Results We observed DNA methylation changes in CpG sites associated with interferon-related genes and genes associated with antigen presentation, concordant with gene expression changes. These changes significantly overlapped with those occurring in bacterial sepsis, although specific DNA methylation alterations in genes specific to viral infection were also identified. We also found these alterations to comprise some of the DNA methylation changes occurring during myeloid differentiation and under the influence of inflammatory cytokines. A progression of DNA methylation alterations in relation to the Sequential Organ Failure Assessment (SOFA) score was found to be related to interferon-related genes and T-helper 1 cell cytokine production. CellPhoneDB analysis of the single-cell transcriptomes of other immune cell types suggested the existence of altered crosstalk between monocytes and other cell types like NK cells and regulatory T cells. Conclusion Our findings show the occurrence of an epigenetic and transcriptional reprogramming of peripheral blood monocytes, which could be associated with the release of aberrant immature monocytes, increased systemic levels of pro-inflammatory cytokines, and changes in immune cell crosstalk in these patients.

Published
2022
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2. Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction

Author

Dieter Weichenhan, Tianlu Li, Felipe Prosper, Sven Kracker, Pere Soler-Palacín, Lennart Hammarström, Andrea Martín-Nalda, Javier Rodríguez-Ubreva, Anne Durandy, Mónica Martínez-Gallo, Romina Dieli-Crimi, Anna G. Ferreté-Bonastre, Pavlo Lutsik, Ángel F. Álvarez-Prado, Laura Ciudad, Bodo Grimbacher, Jacques G. Rivière, Carsten Speckmann, Christoph Plass, Esteban Ballestar, Christian Klemann, Amaya Vilas-Zornoza, Hassan Abolhassani, Francesc Català-Moll, Roger Colobran, Institut Català de la Salut, [Català-Moll F, Ferreté-Bonastre AG, Li T, Ciudad L] Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), 08916 Badalona, Barcelona, Spain. Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L’Hospitalet de Llobregat, Barcelona, Spain. [Weichenhan D, Lutsik P] Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. [Martínez-Gallo M, Dieli-Crimi R] Divisió d’Immunologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Grup de Recerca en Immunologia Diagnòstica, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Rivière JG, Martín-Nalda A, Soler-Palacín P] Unitat de Patologia Infecciosa i Immunodeficiències de Pediatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Grup de Recerca d’Infecció en els Pacients Pediàtrics Immunodeprimits, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Spain. [Colobran R] Divisió d’Immunologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Grup de Recerca en Immunologia Diagnòstica, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Spain. Departament de Biologia Cel·lular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona, Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
AcademicSubjects/SCI00010, Bisulfite sequencing, ADN, Autoimmunity, Cèl·lules B - Immunologia, Hyper-IgM Immunodeficiency Syndrome, 0302 clinical medicine, AID, Activation-induced (cytidine) deaminase, Otros calificadores::Otros calificadores::/inmunología [Otros calificadores], 0303 health sciences, B-Lymphocytes, ADN - Metilació, medicine.anatomical_structure, células::células::células sanguíneas::leucocitos::leucocitos mononucleares::linfocitos::linfocitos B [ANATOMÍA], DNA methylation, Metilació, Rearrangements, Sequencing reveals, Cèl·lules B, Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA::Whole Genome Sequencing [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Naive B cell, Somatic hypermutation, Receptors, Antigen, B-Cell, Biology, Methylation, Cells::Antibody-Producing Cells::B-Lymphocytes [ANATOMY], 03 medical and health sciences, técnicas de investigación::técnicas genéticas::análisis de secuencias::análisis de secuencias de ADN::secuenciación del genoma completo [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Other subheadings::Other subheadings::/immunology [Other subheadings], B-Cell receptor, Cytidine Deaminase, Genetics, medicine, Immune Tolerance, Humans, B cell, Seqüència de nucleòtids, 030304 developmental biology, B cells, Genetic Phenomena::DNA Methylation [PHENOMENA AND PROCESSES], Whole Genome Sequencing, Hypermutation, Gene regulation, Chromatin and Epigenetics, Germinal center, fenómenos genéticos::metilación del ADN [FENÓMENOS Y PROCESOS], DNA, DNA Methylation, Germinal Center, Molecular biology, Induced cytidine deaminase, Demethylation, Super-enhancers, DNA demethylation, biology.protein, Transcription factor, Class-switch recombination, Transcriptome, Immunologic Memory, 030217 neurology & neurosurgery
Abstract

Limfòcits b; Metilació de l'ADN; Genoma Linfocitos b; Metilación de ADN; Genoma B-lymphocytes; DNA methylation; Genome Activation-induced deaminase (AID) initiates antibody diversification in germinal center B cells by deaminating cytosines, leading to somatic hypermutation and class-switch recombination. Loss-of-function mutations in AID lead to hyper-IgM syndrome type 2 (HIGM2), a rare human primary antibody deficiency. AID-mediated deamination has been proposed as leading to active demethylation of 5-methycytosines in the DNA, although evidence both supports and casts doubt on such a role. In this study, using whole-genome bisulfite sequencing of HIGM2 B cells, we investigated direct AID involvement in active DNA demethylation. HIGM2 naïve and memory B cells both display widespread DNA methylation alterations, of which ∼25% are attributable to active DNA demethylation. For genes that undergo active demethylation that is impaired in HIGM2 individuals, our analysis indicates that AID is not directly involved. We demonstrate that the widespread alterations in the DNA methylation and expression profiles of HIGM2 naïve B cells result from premature overstimulation of the B-cell receptor prior to the germinal center reaction. Our data support a role for AID in B cell central tolerance in preventing the expansion of autoreactive cell clones, affecting the correct establishment of DNA methylation patterns. Spanish Ministry of Science, Innovation and Universities [SAF2017-88086-R to E.B.]; cofunded by FEDER funds/European Regional Development Fund (ERDF)—a way to build Europe. E.B is supported by Instituto de Salud Carlos III (ISCIII), Ref. AC18/00057, associated with i-PAD project (ERARE European Union program); P.L. and C.P. are supported by the German Cancer Aid project CO-CLL [70113869]; B.G. is funded by the Deutsche Forschungsgemeinschaft [GR1617/14-1/iPAD, SFB1160/2_B5, RESIST–EXC 2155–Project ID 390874280, CIBSS–EXC-2189–Project ID 390939984]; BMBF [GAIN 01GM1910A]. Funding for open access charge: Spanish Ministry of Science, Innovation and Universities [SAF2017-88086-R].

Published
2021

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