Journal Article

DZNE-2026-00975

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Microglia activation by derepression of endogenous retroviruses drives inflammation and cellular senescence.

Yan, X. (First author)DZNE* ; Georgopoulou, C. (First author)DZNE* ; Lee, H.-m. (First author)DZNE* ; Ahrari, A.DZNE* ; Russ, J.DZNE* ; Chandrasekar, V.DZNE* ; Ducksch, T.DZNE* ; Crispatzu, G.DZNE* ; Talevi, V.DZNE* ; Qiao, L. ; Agrawal, S.DZNE* ; Crux, S.DZNE* ; Daman, A. W. ; Wischhof, L.DZNE* ; Stork, M.DZNE* ; Zweyer, M.DZNE* ; Zanfi, E. D.DZNE* ; Chevallot-Beroux, M.DZNE* ; Li, Y. ; De-Domenico, E.DZNE* ; Hüsson, D.DZNE* ; Bonaguro, L.DZNE* ; Li, Y.DZNE* ; Schulte-Schrepping, J.DZNE* ; Liang, Q. ; Kessler, K. ; Ehninger, D.DZNE* ; Rafii, S. ; Luo, J. ; Hermann, A.DZNE* ; Halle, A.DZNE* ; Liu, Y. ; Mass, E. ; Capasso, M.DZNE* ; Kato, H. ; Schultze, J. L.DZNE* ; Nicotera, P.DZNE* ; Bano, D.DZNE* ; Josefowicz, S. Z. ; Fuhrmann, M.DZNE* ; Ulas, T.DZNE* ; Beyer, M.DZNE* ; Lin, J. ; Breteler, M. M. B.DZNE* ; Aziz, N. A.DZNE* ; Salomoni, P. (Last author)DZNE*

2026
Nature America New York, NY

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Please use a persistent id in citations: doi:10.1038/s41593-026-02404-y

Abstract: Aging-associated loss of chromatin compaction is linked to derepression of retrotransposable elements (RTEs) in mouse and human tissues. Whether such RTE transcription contributes to the microglia activation that is common in aged brains is unknown. Here, we show that DAXX, a histone chaperone and RTE repressor, is downregulated during aging, preserves microglia homeostasis and inhibits cellular senescence. Loss of Daxx in young-adult microglia drives a reactive phenotype marked by chromatin decompaction at RTEs, loss of homeostatic markers, cell cycle re-entry and behavioral changes. This state leads to DNA damage and microglial depletion, followed by replacement with DAXX-deficient/Apoehigh microglia displaying features of senescence. Sustained induction of senescence relies on promyelocytic leukemia protein, a DAXX-interacting factor and interferon target. Together, these findings highlight the importance of heterochromatin maintenance in preserving adult microglial identity and plasticity, with broader implications for brain homeostasis, healthy aging and behavior.

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Contributing Institute(s):

1. Nuclear Function in CNS Pathophysiology (AG Salomoni)
2. Population Health Sciences (AG Breteler)
3. Population & Clinical Neuroepidemiology (AG Aziz)
4. Immunogenomics and Neurodegeneration (AG Beyer)
5. Aging and Neurodegeneration (AG Bano)
6. Translational Biogerontology (AG Ehninger)
7. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)
8. Synaptic Connectivity and Neurodegeneration (AG Nicotera)
9. Immune Regulation (AG Capasso)
10. Microglia and Neuroinflammation (AG Halle)
11. Translational Neurodegeneration (AG Hermann)
12. Molecular and Translational Immunaging (AG Bonaguro)
13. Neuroimmunology and Imaging (AG Fuhrmann)
14. Platform for Single Cell Genomics and Epigenomics (PRECISE)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)
3. 351 - Brain Function (POF4-351) (POF4-351)

Experiment(s):

1. Rhineland Study / Bonn
2. Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn

Appears in the scientific report 2026

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 25 ; JCR ; National-Konsortium ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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