How retrotransposons shape genome regulation

Abstract

Retrotransposons are mutagenic units able to move within the genome. Despite many defenses deployed by the host to suppress potentially harmful activities of retrotransposons, these genetic units have found ways to meld with normal cellular functions through processes of exaptation and domestication. The same host mechanisms targeting transposon mobility allow for expansion and rewiring of gene regulatory networks on an evolutionary time scale. Recent works demonstrating retrotransposon activity during development, cell differentiation and neurogenesis shed new light on unexpected activities of transposable elements. Moreover, new technological advances illuminated subtler nuances of the complex relationship between retrotransposons and the host genome, clarifying the role of retroelements in evolution, development and impact on human disease.

Figure 1. Schematic of human retrotransposons

Retrotransposons (class I transposons) are subclassified into two categories: LTR (Long Terminal Repeats)-retrotransposons, similar to exogenous retroviruses and further divided into multiple sub-families [16], and non-LTR retrotransposons which include LINEs (i.e. L1Hs), SINEs (i.e. Alus) and in humans, SVAs (SINE-VNTR-Alu elements, themselves subdivided into classes A-F). Retroelements are thought to have evolved differently and their proposed origin is reported. The transcriptionally active domains of the different retroelements are also indicated with checkered cylinders (see text). The triangles indicate target site duplications (TSD). The inverted “Alu-like” tag in the figure indicates the inverted orientation of these domains in SVA elements. Abbreviations: UTR= untranslated regions; ORF=open reading frame; EN=endonuclease domain; RT=reverse transcriptase domain; An= A-rich domain; pA=poly A; A B= domains essential for SINE transcription; VNTR= variable number target repeats; Pro= protease; Gag= group-specific antigen (coat protein) gene; Pol=polymerase (reverse transcriptase); Env=envelope gene; IN=integrase.

Figure 2. Retrotransposons shape genome regulation

Retrotransposons contain several DNA controlling elements (transcription/enhancer domain, splicing signals, transcription factor (TF) binding sites, repression signals etc.) mobilized as part of retrotransposon activity in “jumping around” the genome. The immediate effect of retrotransposon activity is usually deleterious for the host cells (see top right insert and [10,13]) and in humans may lead to diseases such as cancer (black arrow). From an evolutionary standpoint retrotransposons can be defined as mutagenic units able to rewire and expand gene regulatory networks (GRNs) (red arrow). Stimuli such as stress, aging and specific developmental cues induce retrotransposon mobilization. Upon jumping, retrotransposon functional units can be exapted by the cell and in some cases retrotransposon features can be “domesticated” and incorporated into host cell functions, such as stem and germ cell regulation.