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Astrocyte Reactivity and Cognitive Decline Follow Chronic Heterochromatin Loss in Neurons

ABSTRACT: 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 results in a chronic inflammatory environment characterized by neurodegeneration and cognitive decline. We discovered differential contributions of HP1 proteins to ERV silencing where HP1γ is necessary and sufficient for H4K20me3 deposition and HP1β deficiency is detrimental to DNA maintenance methylation. Progressive ERV de-repression in HP1β/γ DKO mice was followed by stimulation of the integrated stress response, an increase of Complement 3+ reactive astrocytes and phagocytic microglia. This chronic inflammatory state coincided with age-dependent reductions in dendrite complexity and cognition. Our results demonstrate the importance of preventing loss of epigenetic maintenance, as this will be the only way postmitotic neuronal genomes can be protected and/or renewed.

ORGANISM(S): Mus musculus

PROVIDER: GSE153331 | GEO | 2024/01/10

REPOSITORIES: GEO

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