Recognizing the Sines of Infection: Regulation of Retrotransposon Expression and Modulation of Host Cell Processes

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Recognizing the Sines of Infection: Regulation of Retrotransposon Expression and Modulation of Host Cell Processes viruses Review Recognizing the SINEs of Infection: Regulation of Retrotransposon Expression and Modulation of Host Cell Processes William Dunker 1, Yang Zhao 1, Yu Song 1,2 and John Karijolich 1,3,* 1 Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232-2363, USA; [email protected] (W.D.); [email protected] (Y.Z.); [email protected] (Y.S.) 2 College of Pharmacy, Xinxiang Medical University, Xingxiang 453000, China 3 Vanderbilt-Ingram Cancer Center, Nashville, TN 37232-2363, USA * Correspondence: [email protected]; Tel.: +1-(615)-875-7686 Received: 28 November 2017; Accepted: 17 December 2017; Published: 18 December 2017 Abstract: Short interspersed elements (SINEs) are a family of retrotransposons evolutionarily derived from cellular RNA polymerase III transcripts. Over evolutionary time, SINEs have expanded throughout the human genome and today comprise ~11% of total chromosomal DNA. While generally transcriptionally silent in healthy somatic cells, SINE expression increases during a variety of types of stresses, including DNA virus infection. The relevance of SINE expression to viral infection was largely unexplored, however, recent years have seen great progress towards defining the impact of SINE expression on viral replication and host gene expression. Here we review the origin and diversity of SINE elements and their transcriptional control, with an emphasis on how their expression impacts host cell biology during viral infection. Keywords: retrotransposons; SINEs; gene expression regulation; DNA virus infection; Murine Gammaherpesvirus 68 (MHV68); transcriptional interference; innate immunity 1. Introduction Sequencing of the human genome has determined that approximately 1.5% is exonic, or protein coding [1,2]. While the remaining 98.5% was initially regarded as ‘junk’, it is now widely accepted that the noncoding portion of the genome plays a significant role in diverse cellular processes. The largest contributors to the remaining genome are transposable elements. Transposable elements are classified on the basis of their transposition mechanism. Class I elements, commonly referred to as retrotransposons, mobilize throughout the genome via transcription into RNA intermediates that are reverse-transcribed and inserted at new genomic locations. This mechanism of genomic expansion has been referred to as the “copy-and-paste” method [3]. In contrast, class II elements, or DNA transposons, do not use an RNA intermediate to amplify, but instead “cut-and-paste” themselves by endonucleolytic cleavage of the DNA at the elements’ terminal inverted repeats, and are inserted elsewhere in the genome. Retrotransposons are by far the largest class of transposable elements in the human genome and currently comprise ~45% of the genomic sequence [4]. They can be classified into two major groups: those lacking long terminal repeats (LTRs), which include long and short interspersed elements (LINEs and SINEs, respectively), and those with LTRs, termed endogenous retroviruses (ERVs). Interestingly, ERVs are remnants of past retroviral infections established in the germline of ancestral species [5]. In contrast, SINE elements are derived from the retrotransposition of host encoded RNA polymerase (RNAP) III transcripts, such as tRNA and 7SL RNA [6–9]. The evolutionary biogenesis Viruses 2017, 9, 386; doi:10.3390/v9120386 www.mdpi.com/journal/viruses Viruses 2017, 9, 386 2 of 9 of LINE elements is much less clear. However, LINEs are the most transpositionally active elements in theViruses human2017, 9 ,genome, 386 and facilitate the mobilization of SINEs [10]. LINEs encode for two proteins,2 of 9 open reading frame (ORF) 1 and ORF2, that function as an RNA-binding protein, and an endonucleaseof LINE elements and reverse is much lesstranscriptase, clear. However, respecti LINEsvely. are theBoth most activities transpositionally are required active elementsfor SINE mobilizationin the human [11–13]. genome, and facilitate the mobilization of SINEs [10]. LINEs encode for two proteins, openSINEs reading are expressed frame (ORF) in 1 germ and ORF2, cells thatearly function during as development; an RNA-binding however, protein, andas the an endonucleasecells and the organismand reverse differentiate, transcriptase, the genes respectively. encoding Both SINEs activities beco areme requiredepigenetically for SINE silenced mobilization [14]. Interestingly, [11–13]. many groups,SINEs including are expressed our inown, germ have cells demonstrated early during that development; SINEs regain however, transcriptional as the cells potential and the in variousorganism conditions differentiate, of stress, the including genes encoding viral infection. SINEs become The biological epigenetically significance silenced of [14 their]. Interestingly, expression has manyonly recently groups, includingbecome apparent. our own, Here, have demonstrated we review the that origin SINEs and regain diversity transcriptional of SINE elements potential and in theirvarious transcriptional conditions control, of stress, and including discuss viralhow infection.DNA virus The infection biological impacts significance their expression of their expression and thus influenceshas only host recently cell biology. become apparent. Here, we review the origin and diversity of SINE elements and their transcriptional control, and discuss how DNA virus infection impacts their expression and thus 2. Structureinfluences and host Diversity cell biology. of SINEs 2.The Structure murine and and Diversity human genome of SINEs are estimated to both contain ~1 million SINE loci, comprising ~11% ofThe genomic murine sequence and human [1,2,15]. genome Given are estimated their ancient to both origin, contain SINE ~1 milliongenomic SINE sequence loci, comprising has been subjected~11% oftogenomic extensive sequence mutational [1,2, 15and]. Givenevolutionary their ancient processes, origin, and SINE thus genomic current sequenceSINE elements has been are highlysubjected diverse. to In extensive the Mus mutational musculus genome, and evolutionary there are processes,four major and and thus unrelated current SINE SINE families. elements These are familieshighly are diverse. B1, B2, B4, In theandMus identifi musculuser (ID)genome, [16]. B1 elements there are are four evol majorutionarily and unrelated derived from SINE 7SL families. RNA, the TheseRNA component families are of B1, the B2, signal B4, and recognition identifier particle (ID) [16.]. In B1 contrast, elements B2 are and evolutionarily ID SINEs are derived derived from from ancestral7SL RNA, tRNA the species, RNA componentwhile the B4 of SINE the signal is a ch recognitionimeric tRNA-7SL particle. derived In contrast, SINE B2(Figure and ID1) [6,8,17]. SINEs Of theare murine derived SINEs, from ancestral B1 and B2 tRNA have species, been the while most the extensively B4 SINE is investigated. a chimeric tRNA-7SL derived SINE (FigureIn humans,1)[6,8, the17]. most Of the abundant murine SINEs, SINE is B1 the and Alu B2 element, have been named the most for extensivelyan AluI restriction investigated. site present within theseIn humans, repeats the [18]. most Alu abundant elements SINE are is divided the Alu element,into three named distinct for subfamilies an AluI restriction (Alu J, site Alu present S, and Aluwithin Y). Evolutionarily, these repeats the [18 ].J subfamilyAlu elements arose are first, divided followed into by three the distinctS, and Y subfamilies subfamilies (Alu [10].J, SimilarAlu S, to murineand Alu B1,Y). Evolutionarily,Alu SINEs are theevolutionarily J subfamily arosederived first, from followed 7SL RNA by the (Figure S, and Y1). subfamilies However, [10it ].is importantSimilar to note murine that B1, B1Alu andSINEs Alu evolved are evolutionarily from independent derived from retrotransposition 7SL RNA (Figure events1). However, and are it thus is onlyimportant related in to terms note thatof the B1 RNA and Alu of originevolved [7]. from independent retrotransposition events and are thus only related in terms of the RNA of origin [7]. FigureFigure 1. Origin 1. Origin and and genomic genomic abundance abundance of of major major hu humanman and and murine murine short interspersedinterspersed elementelement (SINE) families. (SINE) families. SINEsSINEs are are short, short, ranging inin length length from from 75–500 75–500 nt, and nt, possess and possess a significant a significant predicated secondarypredicated secondarystructure structure [19]. While [19]. B1 Wh andile B2 B1 RNAs and are B2 monomeric RNAs are inmonomeric structure, Aluin structure,RNAs are dimericAlu RNAs and are composed dimeric 0 andof composed two similar of monomerstwo similar separated monomers by separated an internal by A-rich an internal sequence A-rich (Figure sequence2A–C) [(Figure20]. The 2A–C) 5 -end [20]. of TheSINE 5′-end RNAs of SINE can containRNAs can a triphosphate contain a triphosphate moiety, in part moiety, explaining in part their explaining ability to their elicit ability cell-intrinsic to elicit cell-intrinsicimmune responsesimmune (discussedresponses below).(discussed However, below). some However, B2 SINE some RNAs B2 have SINE been RNAs demonstrated have been to contain gamma-methylphosphate caps, while others are dephosphorylated to a monophosphate via demonstrated to contain gamma-methylphosphate caps, while others are dephosphorylated to a monophosphate via dual specificity phosphatase 11 [21–23]. Importantly, these 5′-end
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