Retrotransposons and Diabetes Mellitus

Abstract

Retrotransposons are invasive genetic elements, which replicate by copying and pasting themselves throughout the genome in a process called retrotransposition. The most abundant retrotransposons by number in the human genome are Alu and LINE-1 elements, which comprise approximately 40% of the human genome. The ability of retrotransposons to expand and colonize eukaryotic genomes has rendered them evolutionarily successful and is responsible for creating genetic alterations leading to significant impacts on their hosts. Previous research suggested that hypomethylation of Alu and LINE-1 elements is associated with global hypomethylation and genomic instability in several types of cancer and diseases, such as neurodegenerative diseases, obesity, osteoporosis, and diabetes mellitus (DM). With the advancement of sequencing technologies and computational tools, the study of the retrotransposon's association with physiology and diseases is becoming a hot topic among researchers. Quantifying Alu and LINE-1 methylation is thought to serve as a surrogate measurement of global DNA methylation level. Although Alu and LINE-1 hypomethylation appears to serve as a cellular senescence biomarker promoting genomic instability, there is sparse information available regarding their potential functional and biological significance in DM. This review article summarizes the current knowledge on the involvement of the main epigenetic alterations in the methylation status of Alu and LINE-1 retrotransposons and their potential role as epigenetic markers of global DNA methylation in the pathogenesis of DM.

Keywords: Alu; DNA methylation; LINE-1; diabetes mellitus; epigenetic modifications; global hypomethylation; nuclear elements; retrotransposons.

Figure 1

Examples of the structure of retrotransposons. (a) Structure of LINE-1: Autonomous elements (such as LINE-1) encode the protein activities essential for retrotransposition, such as a reverse transcriptase and an endonuclease. The arrow at the 5′ end of retrotransposons indicates the transcription start site from their internal promoter. (b) Structure of Alu: Nonautonomous elements (such as Alu) do not encode proteins and their retrotransposition relies on proteins encoded by autonomous elements [15]. ORF: open reading frame; UTR: untranslated-region sequences; EN: endonuclease; Pol II: RNA polymerase II promoter; Pol III: RNA polymerase III promoter (bars labeled A and B); C: denotes cysteine-rich domain (encoded by ORF2); A-rich: adenosine-rich (AR) linker.