Glial 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 HP1{gamma} is necessary and sufficient for H4K20me3 deposition and HP1{beta} deficiency causes aberrant DNA methylation. Combined loss of HP1{beta} and HP1{gamma} resulted in loss of DNA methylation at ERVK elements. Progressive ERV de-repression in HP1{beta}/{gamma} 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/505641v4_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@f5feb7org.highwire.dtl.DTLVardef@25d73dorg.highwire.dtl.DTLVardef@5604a4org.highwire.dtl.DTLVardef@14ad84a_HPS_FORMAT_FIGEXP M_FIG C_FIG