Universität zu Köln

Simonis, Alexander ORCID: 0000-0003-2945-9897, Theobald, Sebastian J., Koch, Anna E. ORCID: 0009-0003-1593-9715, Mummadavarapu, Ram ORCID: 0009-0009-4244-8982, Mudler, Julie M. ORCID: 0000-0003-1378-9648, Pouikli, Andromachi ORCID: 0000-0003-1868-6875, Göbel, Ulrike, Acton, Richard ORCID: 0000-0002-2574-9611, Winter, Sandra, Albus, Alexandra ORCID: 0000-0002-4897-6972, Holzmann, Dmitriy, Albert, Marie-Christine, Hallek, Michael ORCID: 0000-0002-7425-4455, Walczak, Henning ORCID: 0000-0002-6312-4591, Ulas, Thomas, Koch, Manuel ORCID: 0000-0002-2962-7814, Tessarz, Peter ORCID: 0000-0002-6953-9835, Hänsel-Hertsch, Robert ORCID: 0000-0002-2835-4471 and Rybniker, Jan ORCID: 0000-0001-8351-2690 (2025). Persistent epigenetic memory of SARS-CoV-2 mRNA vaccination in monocyte-derived macrophages. Molecular Systems Biology, 21 (4). pp. 341-360. Nature Publishing Group UK. ISSN 1744-4292

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Abstract

Immune memory plays a critical role in the development of durable antimicrobial immune responses. How precisely mRNA vaccines train innate immune cells to shape protective host defense mechanisms remains unknown. Here we show that SARS-CoV-2 mRNA vaccination significantly establishes histone H3 lysine 27 acetylation (H3K27ac) at promoters of human monocyte-derived macrophages, suggesting epigenetic memory. However, we found that two consecutive vaccinations were required for the persistence of H3K27ac, which matched with pro-inflammatory innate immune-associated transcriptional changes and antigen-mediated cytokine secretion. H3K27ac at promoter regions were preserved for six months and a single mRNA booster vaccine potently restored their levels and release of macrophage-derived cytokines. Interestingly, we found that H3K27ac at promoters is enriched for G-quadruplex DNA secondary structure-forming sequences in macrophage-derived nucleosome-depleted regions, linking epigenetic memory to nucleic acid structure. Collectively, these findings reveal that mRNA vaccines induce a highly dynamic and persistent training of innate immune cells enabling a sustained pro-inflammatory immune response.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Simonis, Alexander UNSPECIFIED https://orcid.org/0000-0003-2945-9897 UNSPECIFIED Theobald, Sebastian J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Koch, Anna E. UNSPECIFIED https://orcid.org/0009-0003-1593-9715 UNSPECIFIED Mummadavarapu, Ram UNSPECIFIED https://orcid.org/0009-0009-4244-8982 UNSPECIFIED Mudler, Julie M. UNSPECIFIED https://orcid.org/0000-0003-1378-9648 UNSPECIFIED Pouikli, Andromachi UNSPECIFIED https://orcid.org/0000-0003-1868-6875 UNSPECIFIED Göbel, Ulrike UNSPECIFIED UNSPECIFIED UNSPECIFIED Acton, Richard UNSPECIFIED https://orcid.org/0000-0002-2574-9611 UNSPECIFIED Winter, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Albus, Alexandra UNSPECIFIED https://orcid.org/0000-0002-4897-6972 UNSPECIFIED Holzmann, Dmitriy UNSPECIFIED UNSPECIFIED UNSPECIFIED Albert, Marie-Christine UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, Michael UNSPECIFIED https://orcid.org/0000-0002-7425-4455 UNSPECIFIED Walczak, Henning UNSPECIFIED https://orcid.org/0000-0002-6312-4591 UNSPECIFIED Ulas, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Koch, Manuel UNSPECIFIED https://orcid.org/0000-0002-2962-7814 UNSPECIFIED Tessarz, Peter UNSPECIFIED https://orcid.org/0000-0002-6953-9835 UNSPECIFIED Hänsel-Hertsch, Robert UNSPECIFIED https://orcid.org/0000-0002-2835-4471 UNSPECIFIED Rybniker, Jan UNSPECIFIED https://orcid.org/0000-0001-8351-2690 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-792391
Identification Number:	10.1038/s44320-025-00093-6
Journal or Publication Title:	Molecular Systems Biology
Volume:	21
Number:	4
Page Range:	pp. 341-360
Number of Pages:	20
Date:	25 March 2025
Publisher:	Nature Publishing Group UK
ISSN:	1744-4292
Language:	English
Faculty:	Central Institutions / Interdisciplinary Research Centers External institution Faculty of Medicine
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases Faculty of Medicine > Biochemie > Institut I für Biochemie Faculty of Medicine > Humangenetik > Institut für Humangenetik Faculty of Medicine > Innere Medizin > Klinik I für Innere Medizin - Hämatologie und Onkologie Faculty of Medicine > Sonstiges > Translationale Genomik Faculty of Medicine > Sonstiges > Zentrum für Versorgungsforschung Köln Faculty of Medicine > Zahn-, Mund- und Kieferheilkunde > Zentrum für Zahn-, Mund- und Kieferheilkunde Zentrum für Molekulare Medizin
Subjects:	Life sciences Medical sciences Medicine
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/79239