viruses Review Host Gene Regulation by Transposable Elements: The New, the Old and the Ugly Rocio Enriquez-Gasca y , Poppy A. Gould y and Helen M. Rowe * Centre for Immunobiology, Blizard Institute, Queen Mary University of London, London E1 2AT, UK; [email protected] (R.E.-G.); [email protected] (P.A.G.) * Correspondence: [email protected] These authors contributed equally to this paper. y Received: 17 August 2020; Accepted: 23 September 2020; Published: 26 September 2020 Abstract: The human genome has been under selective pressure to evolve in response to emerging pathogens and other environmental challenges. Genome evolution includes the acquisition of new genes or new isoforms of genes and changes to gene expression patterns. One source of genome innovation is from transposable elements (TEs), which carry their own promoters, enhancers and open reading frames and can act as ‘controlling elements’ for our own genes. TEs include LINE-1 elements, which can retrotranspose intracellularly and endogenous retroviruses (ERVs) that represent remnants of past retroviral germline infections. Although once pathogens, ERVs also represent an enticing source of incoming genetic material that the host can then repurpose. ERVs and other TEs have coevolved with host genes for millions of years, which has allowed them to become embedded within essential gene expression programmes. Intriguingly, these host genes are often subject to the same epigenetic control mechanisms that evolved to combat the TEs that now regulate them. Here, we illustrate the breadth of host gene regulation through TEs by focusing on examples of young (The New), ancient (The Old), and disease-causing (The Ugly) TE integrants. Keywords: gene regulation; transposable elements; endogenous retroviruses; epigenetic repression; Intracisternal A-type particle elements; position-effect variegation; KRAB-associated protein 1; X chromosome inactivation; genomic imprinting 1. Introduction In contrast to their paramount functional importance, protein-coding genes constitute only a small fraction (~2–4%) of the total DNA sequence of the human genome. Exquisitely regulated control of coding genes in time and space is a defining feature of development of multi-cellular organisms. For example, transcription can be regulated by the generation of multiple isoforms of the same gene by alternative splicing, alternative promoter/enhancer usage, non-coding RNAs and epigenetic modifications, which control chromatin structure and function (reviewed in [1]). On the other hand transposable elements (TEs) constitute an estimated two thirds of the human genome [2,3], and contribute to the regulation of protein-coding genes through their regulatory elements. TEs exercise a complex dialog with their host genomes that is distinct from a conventional virus-host arms race because they are not only potential parasites, but also a vital source of genome innovation [4–8]. TEs are subject to epigenetic silencing by histone modifications and DNA methylation [9–11] and become mutated and inactive over the course of evolution. A fraction, however, are co-opted and preserved under purifying selection. In this review, we illustrate how TEs have been co-opted to regulate host genes by focusing on TEs that can alter their surrounding epigenetic context, with our goal to highlight TEs as a normal feature of host gene regulation. The fact that TEs are so ubiquitous in the genome, contain their own Viruses 2020, 12, 1089; doi:10.3390/v12101089 www.mdpi.com/journal/viruses Viruses 2020, 12, 1089 2 of 21 Viruses 2020, 12, x FOR PEER REVIEW 2 of 21 regulatory sequences and have become hotbeds of epigeneticepigenetic regulatory marks, due to theirtheir initialinitial transcriptional silencing, means that they are ideally ideally placed placed to to re-shape re-shape host host gene gene expression expression profiles. profiles. We willwill journeyjourney backback inin timetime toto exploreexplore firstfirst howhow youngyoung oror ‘new’‘new’ TEs, followed by ‘old’ TEs regulate mammalian genes. New TEs are here defineddefined as specificspecific to the primateprimate or murinemurine lineage,lineage, whereas old TEs correspond to those which predate thethe splitsplit betweenbetween mousemouse andand humanhuman ancestralancestral lineageslineages (see(see Figure Figure 1 for examples examples selected selected in in this this review). review). This This distinction distinction allows allows us to us emphasize to emphasize that, while that, whilegene regulatory gene regulatory mechanisms mechanisms involving involving TEs are TEs generally are generally conserved conserved across across species, species, the precise the precise TEs TEsthat thatrewire rewire genes genes are often areoften species-specific. species-specific. This is This due isto duethe different to the di ffTEerent invasions TE invasions that each that species each specieshas encountered. has encountered. We finally We finallyreview reviewinstances instances whereb wherebyy ‘ugly’ ‘ugly’TEs have TEs been have retained been retained by the by host the hostgenome, genome, likely likely due to due them to being them beingbeneficial, beneficial, as well as as well potentially as potentially detrimental detrimental and therefore and therefore discuss discussthe risk thethat risk TE thatco-option TE co-option poses. poses. Figure 1.1. Evolutionary map of example co-opted transp transposableosable elements (TEs) (TEs) for for gene regulation. Clade diagram of of human human and and mouse mouse evolutionary evolutionary traj trajectoriesectories overlaid overlaid with with bubble bubble plots plots showing showing the therelative relative prevalence prevalence of all of allTEs TEs in inthe the human human (blu (blue)e) and and mouse mouse (green) (green) genomes, genomes, according according to their taxonomic specificityspecificity (from(from thethe Dfam database of repetitive DNA families). The dotted line represents an arbitraryarbitrary evolutionaryevolutionary timetime cutocutoffff to to classify classify TEs TEs as as ‘Old’ ‘Old’ vs. vs. ‘New’ ‘New’ in in this this review. review. TEs TEs discussed discussed in thisin this review review are are annotated annotated within within their their respective respective taxa taxa and and colour colour coded coded according according toto theirtheir TETE classclass (see(see thethe key). key). ERV; ERV; endogenous endogenous retrovirus, retrovirus, LINE; longLINE; interspersed long interspersed elements; SINE;elements; short SINE; interspersed short elements,interspersed SVA; elements, SINE/VNTR SVA;/ AluSINE/VNTR/Alu elements. elements. 2. Gene Regulation by Transposable Elements: The New 2. Gene Regulation by Transposable Elements: The New Since the human and mouse lineages diverged from a common ancestor around 80 million years Since the human and mouse lineages diverged from a common ancestor around 80 million years ago, their genomes have been subject to different selective pressures, innovations and invasions. ago, their genomes have been subject to different selective pressures, innovations and invasions. The The present-day human genome has been found to contain no endogenous retroviruses (ERVs) capable present-day human genome has been found to contain no endogenous retroviruses (ERVs) capable of replication/transposition [12], but to host around 100 retrotransposition competent Long INterspersed of replication/transposition [12], but to host around 100 retrotransposition competent Long Element 1s (LINE-1s or L1s) [13]. The human genome is also home to SVA elements, a newly evolved INterspersed Element 1s (LINE-1s or L1s) [13]. The human genome is also home to SVA elements, a newly evolved composite TE derived from SINEs and an ERV (HERV-K10). SVAs harbour a variable number of tandem repeats (VNTRs) and hijack L1 retrotransposition machinery for their Viruses 2020, 12, 1089 3 of 21 Viruses 2020, 12, x FOR PEER REVIEW 3 of 21 composite TE derived from SINEs and an ERV (HERV-K10). SVAs harbour a variable number of tandemmobilisation. repeats With (VNTRs) the youngest and hijack SVA L1 family retrotransposition (SVA_F), around machinery three for million their mobilisation.years old (myo), With SVA the youngestelements SVArepresent family the (SVA_F), youngest around TE in three the huma millionn genome years old [14]. (myo), In contrast, SVA elements the mouse represent genome the youngestappears to TE contain in the humancohorts genome of ERVs [ 14and]. InL1s contrast, capable the of mouseretrotransposition genome appears [15,16]. to containHere, we cohorts inspect of ERVsexamples and L1sof epigenetic capable of retrotranspositioncontrol of host genes [15,16 through]. 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