Regulatory activities of transposable elements: from conflicts to benefits

Abstract

Transposable elements (TEs) are a prolific source of tightly regulated, biochemically active non-coding elements, such as transcription factor-binding sites and non-coding RNAs. Many recent studies reinvigorate the idea that these elements are pervasively co-opted for the regulation of host genes. We argue that the inherent genetic properties of TEs and the conflicting relationships with their hosts facilitate their recruitment for regulatory functions in diverse genomes. We review recent findings supporting the long-standing hypothesis that the waves of TE invasions endured by organisms for eons have catalysed the evolution of gene-regulatory networks. We also discuss the challenges of dissecting and interpreting the phenotypic effect of regulatory activities encoded by TEs in health and disease.

Figure 1. Origins of TE regulatory activities and how they may impact host genes

a | Schematic of major transposable element (TE) classes and their typical genetic organization. The left panel depicts the idealized full-length version of each TE type. Most TEs harbour regulatory sequences that function to promote their own transcription and regulation, such as promoters for RNA polymerase II (Pol II) or RNA polymerase III (Pol III), and polyadenylation signals (PAS). The right panel shows the structures of each type of TEs as they most commonly occur in the genome, which can differ substantially based on the TE (see the main text for details). b | Diagram depicting different types of regulatory activities exerted by TEs. These include effects mediated by cis-regulatory DNA and RNA elements (right panel) as well as trans effects mediated by TE-produced non-coding RNAs and proteins (left panel). c | Hierarchy of evidence to consider when determining if a TE has been co-opted for host functions. Many TEs exhibit biochemical hallmarks of regulatory activity based on genome-wide assays. However, additional evidence is required to determine which of these TEs alter the regulation of host genes and affect organismal phenotype and fitness. Abbreviations: LTRs: long terminal repeats; ERVs: endogenous retrovirus; MITEs: miniature inverted-repeat transposable elements; sRNAs: small RNAs; TIR: terminal inverted repeats.

Figure 2. Examples of phenotypes driven by TE regulatory activity

a | The human pluripotency-associated transcript 5 (HPAT5) is a long non-coding RNA (lncRNA) that is derived from a composite of a HUERS-P1 endogenous retrovirus (ERV) element and an Alu short interspersed nuclear element (SINE). In all figure parts, wavy lines indicate pre-mRNA transcripts and angled lines indicate spliced introns. HPAT5 regulates the let7 family of microRNAs through let7 binding sites carried by the Alu element, and was shown to be essential for inner cell mass formation during early embryonic development. b | A MER41 transposable element (TE) provides an interferon-inducible enhancer upstream of the human AIM2 gene, which regulates inflammation in response to infection. c | In the peppered moth, a polymorphic Carbonaria TE insertion within an intron of the Cortex gene enhances Cortex expression levels (dotted line indicates an uncharacterized regulatory mechanism) which underlay adaptive cryptic colouration during the industrial revolution. d | In oil palm, sporadic demethylation of a Karma TE within an intron of the MANTLED gene results in unmasking of a cryptic splice acceptor site and premature termination signal, causing the mantled fruit phenotype. Left panel depicts genomic locus (not drawn to scale). The fruit images in part d are reproduced from ref

Figure 3. TEs can be aberrantly unmasked to promote disease states

a | Epigenetic perturbations can result in global transposable element (TE) reactivation and pathogenic consequences. The repressive epigenetic marks that normally silence TE transcription include DNA methylation and binding by KRAB zinc finger (ZNF) transcription factors, and these can be depleted upon various stresses. The reactivation of TE sequences across the genome can result in a wide variety of pathogenic consequences, including genome instability via transposition, other pathogenic activities of TE-encoded peptides or non-coding RNAs, and cellular toxicity due to buildup of RNA or cDNA intermediate molecules. b | Studies examining B-cell lymphomas have revealed oncogenic activation of colony-stimulating factor 1 receptor (CSF1R) (driven by a THE1B promoter in Hodgkin Lymphoma), fatty acid-binding protein gene (FABP7) (driven by a LTR2 promoter in diffuse large B-cell lymphoma), and interferon regulatory factor 5 (IRF5) (driven by a LOR1a promoter in Hodgkin Lymphoma). All these examples involve long terminal repeat (LTR) or endogenous retrovirus (ERV) elements, highlighting again the proclivity of this class of TEs to retain potent but generally repressed cis-regulatory activity in the human genome.