Glial reactivity and cognitive decline follow chronic heterochromatin loss in neurons
Newman A.G. Sharif J. Bessa P. Zaqout S. Brown J.P. Richter D. Dannenberg R. Nakayama M. Mueller S. Schaub T. Manickaraj S. Boehm-Sturm P. Ohara O. Koseki H. Singh P.B. Tarabykin V.
December 2025Nature Research
Nature Communications
2025#16Issue 1
In aging cells and animal models of premature aging, heterochromatin loss coincides with transcriptional disruption including the activation of normally silenced endogenous retroviruses (ERVs). Here we show that loss of heterochromatin maintenance and de-repression of ERVs result in a chronic inflammatory environment characterized by neurodegeneration and cognitive decline in mice. We identify distinct roles for HP1 proteins to ERV silencing where HP1γ is necessary and sufficient for H4K20me3 deposition and HP1β deficiency causes aberrant DNA methylation. Combined loss of HP1β and HP1γ results in loss of DNA methylation at ERVK elements. Progressive ERV de-repression in HP1β/γ DKO mice is followed by stimulation of the integrated stress response, an increase of Complement 3+ reactive astrocytes and phagocytic microglia. This chronic inflammatory state coincides with age-dependent reductions in dendrite complexity and cognition. Our results demonstrate the importance of preventing loss of epigenetic maintenance that is necessary for protection of postmitotic neuronal genomes.
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Institute of Cell and Neurobiology, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Developmental Genetics Laboratory, Center for Integrative Medical Sciences (IMS), RIKEN National Research and Development Agency, 1-7-22 Suehiuro-cho, Tsurumi-ku, Kanagawa-ken, Yokohama-shi, Japan
Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
Laboratory of Medical Omics Research, Department of Frontier Research and Development, Kazusa DNA Research Institute, 2-6-7 Kazusa-Kamatari, Chiba, Kisarazu, Japan
Charité-Universitätsmedizin Berlin, Charité 3R – Replace
Charité-Universitätsmedizin Berlin, Department of Experimental Neurology, Center for Stroke Research Berlin, Charitéplatz 1, Berlin, Germany
Charité-Universitätsmedizin Berlin, Charité Core Facility Experimental MRIs, Charitéplatz 1, Berlin, Germany
Department of Applied Genomics, Kazusa DNA Research Institute, 2-6-7 Kazusa-Kamatari, 2, Chiba, Kisarazu, Japan
Department of Biosciences, School of Medicine, Nazarbayev University, 5/1 Kerei, Zhanibek Khandar Street, Astana, Kazakhstan
Institute of Neuroscience, Laboratory of Genetics of Brain Development, National Research Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Avenue, Nizhny Novgorod, 603022, Russian Federation
Institute of Cell and Neurobiology
Developmental Genetics Laboratory
Department of Basic Medical Sciences
Laboratory of Medical Omics Research
Charité-Universitätsmedizin Berlin
Charité-Universitätsmedizin Berlin
Charité-Universitätsmedizin Berlin
Department of Applied Genomics
Department of Biosciences
Institute of Neuroscience
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