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Review
. 2016 Jun 2;62(5):766-76.
doi: 10.1016/j.molcel.2016.03.029.

Long Terminal Repeats: From Parasitic Elements to Building Blocks of the Transcriptional Regulatory Repertoire

Peter J Thompson  1 , Todd S Macfarlan  2 , Matthew C Lorincz  3
Affiliations
Review

Long Terminal Repeats: From Parasitic Elements to Building Blocks of the Transcriptional Regulatory Repertoire

Peter J Thompson et al. Mol Cell. .

Abstract

The life cycle of endogenous retroviruses (ERVs), also called long terminal repeat (LTR) retrotransposons, begins with transcription by RNA polymerase II followed by reverse transcription and re-integration into the host genome. While most ERVs are relics of ancient integration events, "young" proviruses competent for retrotransposition-found in many mammals, but not humans-represent an ongoing threat to host fitness. As a consequence, several restriction pathways have evolved to suppress their activity at both transcriptional and post-transcriptional stages of the viral life cycle. Nevertheless, accumulating evidence has revealed that LTR sequences derived from distantly related ERVs have been exapted as regulatory sequences for many host genes in a wide range of cell types throughout mammalian evolution. Here, we focus on emerging themes from recent studies cataloging the diversity of ERV LTRs acting as important transcriptional regulatory elements in mammals and explore the molecular features that likely account for LTR exaptation in developmental and tissue-specific gene regulation.

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Figures

Figure 1
Figure 1. Structure of an intact ERV and solo LTR and the molecular mechanisms of LTR exaptation as protein-coding or lncRNA promoters
(A) Schematic of non-LTR retrotransposons which include SINEs (i.e. Alus), LINEs (i.e. L1Hs), and SVAs (in humans) and LTR retrotransposons, which include many lineage/species-specific subfamilies. Most LINE elements are truncated at the 5’ end, thus lacking the 5’UTR promoter and TSS. (B) Full-lengthERVs have 5’ and 3’ LTRs, and an “internal” region that includes a primer-binding site (PBS) involved in priming reverse transcription, and retroviral ORFs gag, pol and a truncated or mutated env gene (Δenv). Recombination between 5’ and 3’ LTRs deletes the internal region, generating ‘solo’ LTRs (not to scale), which consist of unique 3’ (U3) and 5’ (U5) regions and a regulatory region (R) containing the TSS (white arrow). LTRs often harbour different combinations of TFBSs (green and orange rectangles) in addition to core Pol II promoter elements (such as TATA box shown in red) and may also contain a splice donor (SD) site (dashed line) within the U5 region. (C) LTR exaptation as a protein-coding gene promoter. In a developmental/tissue specific context, particularly in cell types undergoing epigenetic reprogramming (e.g. early embryo, placenta or germline) a hypomethylated solo LTR (pink rectangle) 5’ of a protein-coding gene (or in an intragenic region) may become exapted as a novel promoter (black circles represent DNA methylation). The process may involve base substitutions in a neighbouring near-consensus TFBS (grey rectangle with dash outline) and a near-consensus site within the LTR (green rectangle with dash outline), which then form a positive genetic interaction with another LTR-derived TFBS (orange rectangle) a mechanism termed ‘epistatic capture’ (Emera and Wagner, 2012a). This leads to synergy in the binding of several TFs (grey, orange and green ovals), deposition of “active” histone modifications, such as H3K4me3 and H3K9ac (green circles) and robust transcription initiation from the LTR-derived promoter. The canonical genic promoter may be DNA methylated as a consequence of such transcription. This process generates LTR-genic exon chimeric transcripts, where exon 1 is derived from the LTR and splicing occurs from the internal LTR SD (or from a cryptic SD site in the intervening genomic sequence downstream of the active LTR) to the first downstream exon with a splice-acceptor site, generally exon 2. Examples of such chimeric transcripts include Spin1 in mouse and CSFR1 and B3GALT5 in human. Arrow sizes indicate relative level of transcription from each promoter. (D) LTR exaptation as a promoter for a novel lncRNA. Through a process as in (C), a newly formed intergenic solo LTR without an SD site could initiate de novo lncRNA transcription, forming a novel lncRNA gene. An example of this is the lincRNA-RoR transcript.
Figure 2
Figure 2. Molecular mechanisms of exaptation of LTRs as enhancers
LTRs located both proximal or distal, (i.e. >10 kb) to a genic promoter may be exapted as enhancer elements. Such elements may be solo LTRs (shown) or intact ERVs. While these LTRs may have intrinsic enhancer activity, base substitutions that generate additional TF binding sites (potentially synergizing with pre-existing sites), may over time increase overall enhancer activity and/or refine tissue specificity. Note that in contrast with LTR-derived genic promoters, which are generally in the sense orientation, an LTR integrated in either orientation with respect to the relevant gene could be exapted as an enhancer. Robust enhancer activity also likely requires formation of an open chromatin structure and the generation of enhancer RNA transcripts (eRNAs) in the relevant cell type. The strong association of specific histone marks with enhancers, including H3K4me1 (light green circles) and H3K27ac (yellow triangles), the latter indicative of “active” enhancers, has been widely exploited to identify novel candidate enhancers, including within LTRs. Examples of LTR enhancers include BGLII and LTR17 and perhaps LTR13D5 and LTR9, but whether these latter two LTRs produce eRNAs has not been determined.
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