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Review
. 2022 Jul;23(7):481-497.
doi: 10.1038/s41580-022-00457-y. Epub 2022 Feb 28.

Roles of transposable elements in the regulation of mammalian transcription

Raquel Fueyo #  1 , Julius Judd #  2 , Cedric Feschotte  3 , Joanna Wysocka  4   5   6   7
Affiliations
Review

Roles of transposable elements in the regulation of mammalian transcription

Raquel Fueyo et al. Nat Rev Mol Cell Biol. 2022 Jul.

Abstract

Transposable elements (TEs) comprise about half of the mammalian genome. TEs often contain sequences capable of recruiting the host transcription machinery, which they use to express their own products and promote transposition. However, the regulatory sequences carried by TEs may affect host transcription long after the TEs have lost the ability to transpose. Recent advances in genome analysis and engineering have facilitated systematic interrogation of the regulatory activities of TEs. In this Review, we discuss diverse mechanisms by which TEs contribute to transcription regulation. Notably, TEs can donate enhancer and promoter sequences that influence the expression of host genes, modify 3D chromatin architecture and give rise to novel regulatory genes, including non-coding RNAs and transcription factors. We discuss how TEs spur regulatory evolution and facilitate the emergence of genetic novelties in mammalian physiology and development. By virtue of their repetitive and interspersed nature, TEs offer unique opportunities to dissect the effects of mutation and genomic context on the function and evolution of cis-regulatory elements. We argue that TE-centric studies hold the key to unlocking general principles of transcription regulation and evolution.

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Conflict of interest statement

Competing interests

The authors declare no competing interests.

Figures

Fig. 1 |
Fig. 1 |. Major types of TEs in mammalian genomes.
Transposable elements (TEs) are divided into Class I and Class II depending on their transposition mechanism. Class I elements are called retrotransposons because they use RNA as an intermediate that is reverse transcribed into DNA and integrated in the genome (not shown). a | Autonomous retrotransposons encode all the required proteins for their retrotransposition. Endogenous retroviruses (ERVs) consist of two long terminal repeats (LTRs) flanking the open reading frames (ORFs) that encode the viral proteins. During evolution, ERVs are often reduced to a single LTR, or ‘solo LTR’, which renders them incapable of retrotransposition. Long interspersed nuclear elements (LINEs), such as L1, contain two ORFs that encode proteins required for their retrotransposition, which are flanked by untranslated regions (UTRs). At the 3′ end, they possess an adenines tail of variable length. b | Non-autonomous retrotransposons comprise those TEs that require the machinery encoded by autonomous retrotransposons to be mobilized (the TEs depicted here use the L1 machinery). Alu elements are primate-specific short interspersed nuclear elements (SINEs), and their structure consists of two monomers derived from the 7SL non-coding RNA, flanking an adenine (A)-rich region. At the 3′ end, they possess an adenines tail of variable length. On the left monomer, boxes A and B indicate a bipartite promoter for RNA polymerase III (Pol III). SINE-VNTR-Alu (SVA) elements are hominoid-specific composite non-autonomous retrotransposons comprised of a 5′ region of a variable number of repeats of the hexamer CCCTCT, followed by an Alu-like region, a variable number of tandem repeats (VNTR), and a 3′ ‘SINE-R’ region derived from the LTR of human endogenous retrovirus K. c | Class II DNA transposons encode a transposase that is required for their excision and insertion through a ‘cut-and-paste’ mechanism. The transposase ORF is flanked by two inverted terminal repeats (ITRs). Asterisk indicates that the precise localization of the cis-regulatory feature within the delimited region is unknown. Numbers in brackets indicate the percentage of the human genome (chm13-v1.0 (REF.)) comprised by the specific subfamily. env, envelope; pol, reverse-transcriptase; pro, protease.
Fig. 2 |
Fig. 2 |. Overview of mechanisms by which TEs influence host transcription regulation.
a | Transposable elements (TEs) can introduce new enhancers or promoters of cellular genes. A TE is depicted providing a transcription factor binding site (TFBS), which influences the transcription of the gene. b | TEs modulate 3D chromatin structure. A TE is depicted providing a TFBS for CCCTC-binding factor (CTCF), thereby demarcating a new boundary between two topologically associating domains (TADs; represented as dark-red triangles in a Hi-C map). c | TEs give rise to novel nuclear long non-coding RNAs (lncRNAs). A TE-derived non-coding RNA serves as a scaffold for a transcription factor that modulates the expression of a nearby gene in cis or of another gene in trans. d | TEs generate new transcription factors by fusion of DNA-binding domains of their transposase (TPase) with host transcription factor domains. A transposase-transcription factor fusion is depicted modulating two genes as a result of its binding to cognate TE sequences in the genome. e | Collateral effects of TE silencing on host gene transcription. A TE is bound by a host repressive transcription factor, thereby causing the silencing of nearby gene.
Fig. 3 |
Fig. 3 |. Examples of families of TEs in humans and mice that may have cis-regulatory functions based on the binding of specific TFs or on functional experiments.
a | During human embryonic development and in human differentiated tissues,–,,,,,,,,,–. b | During mouse embryonic development and in mouse differentiated tissues,,,,,,,,,,,. The figure shows how the transposable elements (TEs; dark grey boxes) that exhibit cis-regulatory activity at different stages of the life of an organism (namely humans and mice) differ in their characteristics. TEs that are active during early embryonic development belong to evolutionarily young families, whose sequences are nearly identical to their ancestral TE sequence. As a consequence, these elements share transcription factor (TF) binding sites and are often co-regulated. As development proceeds, the TEs that become active belong to evolutionarily older families and their DNA sequences frequently diverge from the ancestral sequence. In contrast to the co-regulation of the young TEs, only specific copies of these older TEs become active in the different tissues. Asterisk indicates that the specific member of the family of TFs that activates the reporter was not specified. Only the cis-regulatory activity of TEs and TFs demonstrated by genetic manipulation, reporter assay or chromatin immunoprecipitation (ChIP), is depicted. CDX2, caudal type homeobox 2; ELF5, E74-like factor 5; EOMES, eomesodermin; FOXO1A, Forkhead box O1; HERV-K: human endogenous retrovirus type K; KLF4, Krüppel-like factor 4; LTR, long terminal repeat; LTR5HS, long terminal repeat 5 human specific; MER41, medium reiterated sequence 41; MTC, mouse transcript family type C; OCT4, octamer-binding transcription factor 4; SOX2, SRY-box transcription factor 2; SVA, SINE-VNTR-Alu; TFCP2L1, transcription factor CP2-like 1.
Fig. 4 |
Fig. 4 |. Transposable element insertional polymorphisms that drive cis-regulatory changes and their phenotypic association in GWAS.
a | In neurons, a human endogenous retrovirus type-K (HERV-K) polymorphic insertion located between exons 9 and 10 of the gene encoding the C4A and C4B complement components promotes its transcriptional upregulation. The complement component signalling pathway is associated with synaptic pruning, and the HERV-K-containing C4A and C4B gene variants have been associated with schizophrenia. b | Also in neurons, a sole long terminal repeat (LTR5HS) of HERV-K located at the RASGRF2 gene (encoding Ras-specific guanine nucleotide releasing factor 2) ~194 kb away from the promoter, leads to an increase in RASGRF2 expression. RASGRF2 is required for dopamine release, and this LTR5HS polymorphism has been associated with drug abuse. GWAS, genome-wide association studies.
Fig. 5 |
Fig. 5 |. Use of TEs as a model system for studying transcription regulation.
a | The dispersed, repetitive nature of transposable elements (TEs) enables large-scale sequence-specific transcriptional alterations using catalytically dead Cas9 (dCas9) fused to a transcription factor (domain). In the case of dCas9 fusion to a transcription activator, a minimal number of guide RNAs (gRNAs) complementary to a highly repetitive TE family can enable simultaneous transcriptional perturbation of many individual TE loci. b | The repetitive nature of TE families allows discrimination between the effects of subtle changes in sequence on transcription factor binding and regulatory activity. c | TEs enable the study of how the genomic context of a regulatory element influences its activity and evolution. A TE that inserted near a pre-existing transcription factor binding site (TFBS) gains an additional TFBS for the same transcription factor by point mutation. This process can result in either cis-regulatory fine-tuning, owing to the addition of a second binding site with similar activity; cis-regulatory redundancy, which can buffer against harmful regulatory changes introduced by future mutations; or cis-regulatory turnover, where introduction of the second TFBS relaxes selection on the pre-existing TFBS, which then decays by mutation and leaves the new nearby TE-derived TFBS in its place. A TE that gains a TFBS with no pre-existing TFBS nearby has two outcomes: the introduction of a cis-regulatory innovation, where new activity arises de novo, or the activity is deleterious and is purged by selection. ChIP, chromatin immunoprecipitation.
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