Role of Transposable Elements in Genome Stability: Implications for Health and Disease

Abstract

Most living organisms have in their genome a sizable proportion of DNA sequences capable of mobilization; these sequences are commonly referred to as transposons, transposable elements (TEs), or jumping genes. Although long thought to have no biological significance, advances in DNA sequencing and analytical technologies have enabled precise characterization of TEs and confirmed their ubiquitous presence across all forms of life. These findings have ignited intense debates over their biological significance. The available evidence now supports the notion that TEs exert major influence over many biological aspects of organismal life. Transposable elements contribute significantly to the evolution of the genome by giving rise to genetic variations in both active and passive modes. Due to their intrinsic nature of mobility within the genome, TEs primarily cause gene disruption and large-scale genomic alterations including inversions, deletions, and duplications. Besides genomic instability, growing evidence also points to many physiologically important functions of TEs, such as gene regulation through cis-acting control elements and modulation of the transcriptome through epigenetic control. In this review, we discuss the latest evidence demonstrating the impact of TEs on genome stability and the underling mechanisms, including those developed to mitigate the deleterious impact of TEs on genomic stability and human health. We have also highlighted the potential therapeutic application of TEs.

Keywords: DSB; genome; stability; transposons.

Figure 1

Classification of human transposons.

Figure 2

TE-regulated mechanisms of action in the host cells. (1) Cis-regulatory mechanisms involving (A) promoter and (B) enhancer, integrate the activity of specific transcription factor; (C) insulator, act either through enhancer-blocking activity or chromatin barrier activity; (D) silencer, silence the expression of genes. (2) Retrotransposon mechanism can increase the potential of transcription binding factor. (orange arrowhead indicates increased activity, blue cross indicates silencing of activity, circle with single cross indicates insulation of gene activity, grey arrow indicates direction of action).

Figure 3

Regulation of TEs in the normal and cancer cell. In normal cells (left panel), epigenetic modifications like DNA methylation, histone modification, and non-coding RNA, silence the activity of TEs. In cancer cells (right panel) hypomethylation, different histone modification, and non-coding RNAs cause removal of repressive signals and unregulated expression of TEs. This leads to degradation of DNA, mutations, and genomic instability (orange arrowhead indicates the increased activity, blue circle indicates histone, orange circle indicates methyl groups, blue cross indicates silencing).

Figure 4

Potential applications of TEs in biological science and human health.