NeurotoxicDosesofChronicMethamphetamine TriggerRetrotranspositionoftheIdentifierElement inRatDorsalDentateGyrus.

Anna Moszczynska,Kyle Burghardt,Dongyue Yu

doi:10.3390/genes8030096

Anna Moszczynska, Kyle Burghardt + Show 1 more

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https://doi.org/10.3390/genes8030096

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Abstract

Short interspersed elements (SINEs) are typically silenced by DNA hypermethylation in somatic cells, but can retrotranspose in proliferating cells during adult neurogenesis. Hypomethylation caused by disease pathology or genotoxic stress leads to genomic instability of SINEs. The goal of the present investigation was to determine whether neurotoxic doses of binge or chronic methamphetamine (METH) trigger retrotransposition of the identifier (ID) element, a member of the rat SINE family, in the dentate gyrus genomic DNA. Adult male Sprague-Dawley rats were treated with saline or high doses of binge or chronic METH and sacrificed at three different time points thereafter. DNA methylation analysis, immunohistochemistry and next-generation sequencing (NGS) were performed on the dorsal dentate gyrus samples. Binge METH triggered hypomethylation, while chronic METH triggered hypermethylation of the CpG-2 site. Both METH regimens were associated with increased intensities in poly(A)-binding protein 1 (PABP1, a SINE regulatory protein)-like immunohistochemical staining in the dentate gyrus. The amplification of several ID element sequences was significantly higher in the chronic METH group than in the control group a week after METH, and they mapped to genes coding for proteins regulating cell growth and proliferation, transcription, protein function as well as for a variety of transporters. The results suggest that chronic METH induces ID element retrotransposition in the dorsal dentate gyrus and may affect hippocampal neurogenesis.

Highlights

Transposable elements are non-coding pieces of DNA with the ability to “jump” to different locations in the genome upon activation [1]
The present study demonstrates that neurotoxic doses of binge and chronic METH regimen differentially affected the CpG methylation within the ID element sequence at 1 h after METH; binge
Our results suggest that high-dose chronic METH triggers a chain of events leading to ID element retrotransposition in the dentate gyrus and that the ID element may play a role in METH-mediated changes in hippocampal neurogenesis

Summary

Introduction

Transposable elements are non-coding pieces of DNA with the ability to “jump” to different locations in the genome upon activation [1]. They can control genes epigenetically when inserted (transposed) into genes or gene regulatory regions. Short interspersed elements (SINEs) are non-autonomous transposable elements known as short retrotransposons [8] They are short DNA sequences with a length of 80–400 bp that are dispersed over the eukaryotic genome, are amplified by a reverse transcription and retrotranspose by a copy-and-paste mechanism [9]

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