Retrotransposons as regulators of gene expression

Parasitic DNAs help and hinder evolution Transposable elements are parasitic DNAs that can duplicate themselves and jump around their host genomes. They can both disrupt gene function and drive genome evolution. Elbarbary et al. review the roles of two classes of transposable elements in gene regulation and disease: long interspersed elements (LINEs) and short interspersed elements (SINEs). Roughly a third of the human genome consists of LINEs and SINEs. They contribute to a broad range of important genome and gene regulatory features, while at the same time being responsible for number of human diseases. Science, this issue p. 10.1126/science.aac7247 BACKGROUND Genomes are subject to two types of changes: changes to the DNA sequence, and changes that are epigenetic in nature. Changes to the DNA sequence can result from errors made during DNA replication and/or repair, or from the insertion of mobile DNA. Mobile DNAs, also called transposable elements (TEs), have the potential to provide regulatory and/or protein-coding sequences at a new integration site. Depending on its nucleotide sequence and genomic insertion site, an individual TE can disrupt gene expression, directly or indirectly create an advantageous modification to gene expression, or be of no immediate consequence. Changes can be genetic, epigenetic, or both. In this way, TEs are molecular parasites and evolutionary drivers, each role originating from the ability to insert into, spread through, and restructure genomes. This review focuses on the types of TEs that transpose via RNA intermediates—retrotransposons—that are not bounded by long terminal repeats. The most abundant retrotransposons in animal genomes come in two forms: long interspersed elements (LINEs) and short interspersed elements (SINEs). ADVANCES The advent of deep genomic and transcriptomic sequencing, together with studies of individual LINE or SINE functions, has led to a greater appreciation of how the two TEs influence gene expression. Our review focuses principally on data that derive from human and mouse studies. These data demonstrate that LINEs and SINEs perform many diverse roles within cells. As DNA sequences, they can regulate gene transcription by altering chromatin structure and by functioning as enhancers or promoters. When transcribed as part of a larger transcript, they can create new transcript isoforms (by influencing alternative pre-mRNA splicing or 3′-end formation), alter mRNA localization, change mRNA stability, tune the level of mRNA translation, or encode amino acids that diversify the proteome. Further, the RNA transcripts of LINEs or SINEs may themselves function to regulate gene expression. Through their various roles, TEs influence many aspects of cellular metabolism, including the ability to divide, migrate, differentiate, and respond to stress. OUTLOOK TEs continue to spread throughout our genomes in both gametes and somatic tissues, introducing new gene regulatory activities or causing disease. Although deep transcriptome sequencing has identified a myriad of SINE-containing noncoding RNAs, the functional importance of most of these transcripts remains unknown. Additionally, we need to understand the consequence of the very high degree of TE transposition in our brains. We also need to uncover the determinants that influence the effect of a specific SINE on gene expression, and, given that different organisms can contain SINEs of distinct origins, the extent to which these SINEs contribute to species-specific differences. Moreover, it will be important to determine the extent to which independently evolved SINEs have been co-opted for similar functions. Some of the steps in the expression of mammalian genes that can be affected by cis- or trans-acting LINEs or SINEs. LINE and SINE genomic insertions can regulate gene expression by altering transcription and/or chromatin structure. When embedded in the transcripts of RNA polymerase II (Pol II)–transcribed genes, SINEs can influence nuclear pre-mRNA splicing, nuclear mRNA retention in paraspeckles, cytoplasmic mRNA stability, or cytoplasmic mRNA translation. ARE-BP, AU-rich element–binding protein. ILLUSTRATION: K.SUTLIFF/SCIENCE Transposable elements (TEs) are both a boon and a bane to eukaryotic organisms, depending on where they integrate into the genome and how their sequences function once integrated. We focus on two types of TEs: long interspersed elements (LINEs) and short interspersed elements (SINEs). LINEs and SINEs are retrotransposons; that is, they transpose via an RNA intermediate. We discuss how LINEs and SINEs have expanded in eukaryotic genomes and contribute to genome evolution. An emerging body of evidence indicates that LINEs and SINEs function to regulate gene expression by affecting chromatin structure, gene transcription, pre-mRNA processing, or aspects of mRNA metabolism. We also describe how adenosine-to-inosine editing influences SINE function and how ongoing retrotransposition is countered by the body’s defense mechanisms.