Activity-DEPendent Transposition

Abstract

The authors propose a novel mechanism, termed Activity‐DEPendent Transpositon (ADEPT), in which epigenetic drift and the preferential use of homologous‐directed repair allows transposable elements to hijack activity‐induced double‐strand breaks in aged neurons, contributing to neurodegenerative disease.

Figure 1

Age‐related augmentation of Activity‐DEPendent Transposition.Upon stimulation, neurons induce DNA double‐strand breaks (DSBs) in the enhancer/promoter region of immediate‐early genes (middle panel), a known requirement for their expression. Left column: In young neurons, these activity‐induced DSBs are repaired by the non‐homologous end‐joining (NHEJ) pathway (bottom panel) 1. Right column: In aged neurons, epigenetic drift results in poor definition of chromatin compartments as defined by histone modifications and DNA methylation. Active marks such as H3K4me1 and H3K4me3 no longer sharply define promoters or the transcription start site (TSS). In the vicinity of the enhancer/promoter DSB region, an “epigenetic scar” is likely to form, due to improper re‐establishment of epigenetic marks following a lifetime of DNA repair. Repetitive sequences are no longer repressed by H3K9me3 and DNA methylation, resulting in their transcription as lncRNA. It is a likely scenario that this epigenetic drift diverts DNA repair toward transcription‐coupled homologous recombination (TCHR), which uses the available repeat‐rich lncRNA as a template. Homologous recombination is permissive between homologous repetitive elements flanking genic exons, most often resulting in (a) large deletions or (b) alternative TSS generation or alternative splicing due to loss of one exon. Insertions (c) or duplications into the enhancer/promoter region may also occur at a higher frequency with diminished DSB repair efficacy and higher abundance of transposable elements and repeat sequences.