CTRL+INSERT: retrotransposons and their contribution to regulation and innovation of the transcriptome

Abstract

The human genome contains millions of fragments from retrotransposons-highly repetitive DNA sequences that were once able to "copy and paste" themselves to other regions in the genome. However, the majority of retrotransposons have lost this capacity through acquisition of mutations or through endogenous silencing mechanisms. Without this imminent threat of transposition, retrotransposons have the potential to act as a major source of genomic innovation. Indeed, large numbers of retrotransposons have been found to be active in specific contexts: as gene regulatory elements and promoters for protein-coding genes or long noncoding RNAs, among others. In this review, we summarise recent findings about retrotransposons, with implications in gene expression regulation, the expansion of gene isoform diversity and the generation of long noncoding RNAs. We highlight key examples that demonstrate their role in cellular identity and their versatility as markers of cell states, and we discuss how their dysregulation may contribute to the formation of and possibly therapeutic response in human cancers.

Keywords: endogenous retrovirus; lncRNA; regulation; retrotransposon; transcription.

Figure 1. Retrotransposon classes, naming and genomic distribution

(A) The contribution of the three major classes of retrotransposons to the human genome sequence. (B) Each retrotransposon class contains several families; shown is the relative contribution of each family to the respective retrotransposon class. (C) Each family contains several subfamilies; the relative contribution to the families is shown, and selected examples are highlighted. (D) Shown are all HERVH fragments on chromosome 2. (E) Visualisation of a LTR7B‐HERVH retrotransposon on chromosome 2 consisting of the two flanking LTR elements and the internal HERVH element. (F) Model for ERVs. Three genes (Gag, Pol, Env) are surrounded by two long terminal repeats (LTRs) that contain a promoter. (G) Model for LINEs. Human LINE 1 elements contain 2 (sometimes 3) open reading frames (ORFs), which are regulated by two promoters. (H) Model of SINEs and SVAs. Unlike the other retrotransposons, SINEs do not contain protein‐coding genes. SVAs are a combination of SINEs and ERVs.

Figure 2. ERVs regulate and expand the transcriptome

(A) ERVs can act as enhancers, regulating genes in the proximity. (B) ERVs can act as alternative promoters for protein‐coding and noncoding genes. (C) ERVs can provide the only promoter for a gene; such ERV‐derived genes are largely noncoding. (D) ERVs can be transcribed over their full length. Transcribed ERVs can generate proteins and peptides, but they can also generate noncoding RNAs.

Figure 3. Specific ERVs mark the different cellular identities in early embryonic development

(A) Specific ERV families are expressed in the early human embryo, and in naïve and primed human embryonic stem cells (ESCs). (B) In mouse, it was found that ERVs are specifically activated in the two‐cell stage. These ERVs are spontaneously expressed in cells which show features of two‐cell‐like totipotent cells.