Activity-DEPendent Transposition.

Abstract

The fundamental unit of the brain, the neuron, has a remarkable ability to respond to environmental stimuli. Neuronal stimulation results in rapid transcriptional changes in immediate‐early (IE) genes. Their regulation has been the focus of intense research, which revealed that enhancer/promoter activity of IE genes is facilitated by topoisomerase IIβ‐mediated induction of double‐strand breaks (DSBs) [1]. Building on these data, we suggest a novel mechanism, termed Activity‐DEPendent Transposition (ADEPT). We propose that DSBs resulting from neuronal activity are exploited by transposable elements (TEs) to generate adaptive somatic mosaicism in adult neurons, which is distinct from the well‐documented developmental somatic mosaicism seen during neurogenesis. The genomic rearrangements caused by ADEPT can lead to either de novo integration of transposable elements or homology‐directed recombination of repetitive sequences contained within the transposable elements. In our opinion, the evidence in favor of ADEPT is mounting and carries considerable importance for neuronal plasticity, neural network adaptation, and, importantly, genome stability in the aging brain. Transposable elements are mobile genetic elements that comprise 40–50% of the mouse and human genomes and are known to harbor eukaryotic transcription factor binding sites (TFBS). After germline integration, newly available TFBS can be exaptated as species‐ or tissue‐specific transcriptional enhancers [2]. Several studies have confirmed copy number and TE integration loci to vary significantly between individual neurons, a developmental somatic mosaicism that appears to occur during neurogenesis [3]. This has led to the notion that somatic mosaicism is generated in large part by de novo insertions of LINE retrotransposons (long interspersed nuclear elements) in neurons while undergoing the last neural progenitor divisions. As a population, neurons with high or low TE insertions may express different subsets of ion channels or neuronal adhesion molecules and thus have different firing properties. The generation of such a diverse …