Controlling and controlled elements: highlights of the year in mobile DNA research

As the year 2024 comes to a close, the Editors-in-Chief of Mobile DNA are pleased to present a selection of topics which fascinated them during the year and opened new perspectives for further developments in the field. Investigations of transposable elements (TE), aka mobile genetic elements (MGE), which were discovered by Barbara McClintock as ‘controlling elements’ and are found in all domains and kingdoms of life, span multiple scientific disciplines and get published in a broad range of scientific journals. As the flagship open-access journal for MGE research, now celebrating the 15th anniversary since its launch in 2010 [1], Mobile DNA prides itself on community-organizing aspects of its operation, such as thematic collections on popular topics or data analysis tools, and publication of meeting reports which play an important role of informing researchers all over the world about developments in the field and ongoing discussions. In 2024, such report was published for the International Congress on Transposable Elements (ICTE), which took place in Saint Malo, France, on April 20–23 [2].

The power and complexity of TE research lies in its embrace of virtually all aspects of biology and in the fact that it attracts scientists from all walks of life, including but not limited to evolutionary and population geneticists, microbiologists and virologists, structural and systems biologists, computational biologists, neuroscientists, developmental and cell biologists, and biomedical and physician-scientists. TE-related papers published in 2024 in various biological journals cover topics ranging from structural and mechanistic aspects of transposition to the variety of genetic and epigenetic mechanisms of TE silencing, structural variation within and between species and natural populations, environmental factors affecting TE transmission, expression and transposition, new and improved methods of TE detection and annotation, and the use of TEs as tools for genome editing and engineering. While it is not possible to summarize information from hundreds of papers on the above topics in a single editorial, here we highlight some of the editors’ favorite articles that reflect major directions currently pursued by research groups of diverse expertise and published in journals of every scope, from multidisciplinary to specialty.

Mobile DNA tools

Traditionally a subject area of special interest to the journal readership, this is a permanent Collection continuously open for submission. Studies of TEs in any given organism begin with their proper identification and annotation, though methods employed for short-read genome assemblies have often misinterpreted longer, highly-identical TEs. Fortunately, with the advent of long-read, chromosome-scale assemblies, TE detection approaches relying on repetitiveness, homology and/or structural features can now be complemented with methods based on detecting indel polymorphisms in multiple independently sequenced genomes of the same species (pangenomes), or in sets of closely related species. The recently developed toolkits called Pantera [3], GraffiTE [4] and Pannagram [5] are perfectly suited for detecting active TEs, which can be large and/or low-copy, in pangenomes.

Understudied genome compartments

New sequencing strategies have re-invigorated studies of the highly repetitive regions of the genome, which were previously hidden from view. Emergence of numerous chromosome-scale assemblies, in many cases of telomere-to-telomere quality with no gaps, stimulated researchers to interrogate the properties of TE insertions in rDNA, centromeres, (sub)telomeres, and other satellite repeats. Interestingly, centromeres of a diploid wheat species lack tandem repeat arrays and are instead composed of two centromere-specific LTR-retrotransposon families forming a pair in which enzymatic functions are provided by pol in the autonomous family, and gag nucleocapsid by the non-autonomous family [6], analogous to the Drosophila telomeric non-LTR retrotransposon system. Moreover, a rapid turnover between retroelements and satellite DNAs is observed over short evolutionary timescales in the simulans clade of Drosophila [7]. In Drosophila rDNA arrays, expression of R2 non-LTR retrotransposon insertions is repressed by insulin receptor, preventing uncontrolled rDNA copy number expansion in the germ line [8].

From conflict to cooperation, via addiction, co-option or domestication

The spectrum of TE-host relationships is very broad, and while most insertions are deleterious or neutral, some do evolve to provide benefits to the host via repurposing of regulatory elements, coding sequences, or parts thereof. Continuing the topic of centromeres, in the plant Arabidopsis proper segregation of chromosome 5 is dependent on epigenetic silencing of centromeric LTR-retrotransposon Athila, showing that centromeres can become ‘addicted’ to invading retrotransposons [9]. Retrotransposon activity has been associated with emergence and spread of an environment-sensitive allelic variant, enabling Arabidopsis to enhance its adaptation to herbicide [10]. The vertebrate immune system has been continuously shaped by transposon recruitment, and a recent example is provided by co-option of a TE-derived exon into a type I interferon receptor, forming a decoy receptor that regulates interferon signaling [11]. On a broader scale, TE exonization provides a sizeable reservoir of protein isoforms for natural selection in humans [12], and should be more amenable to experimental validation in other species.

Controlled by the host

The necessity to control ‘controlling elements’ often leads to accumulating several layers of control mechanisms, superimposed onto each other. Transcriptional silencing is driven by piRNAs, which in mammals direct methylation of young LINE elements; however, to achieve precise methylation, a chromatin reader SPIN1 recognizing dual chromatin marks at young active LINEs needs to be recruited first, in a process the authors call two-factor authentication [13]. The interaction of human L1 with its flanking genomic sequences, which is influenced by epigenetic factors, affects both the activity of L1 elements and the function of the human genome [14], whereby L1 elements controlled by the host are in turn controlling adjacent genes. Interestingly, host control systems can also compete: LINEs are repressed by the HUSH complex, but interferon-stimulated genes are repressed by a different HUSH2 complex with shared components, linking immune response and LINE derepression [15].

Bacterial defense mechanisms

Out of numerous defense systems in bacteria identified in earlier studies, at least six showing antiviral properties were associated with unknown types of reverse transcriptases (RTs), however their mechanisms of action remained elusive. One of these systems, DRT2 (or UG2), is now shown to encode, in antisense orientation, a small building block of a toxic repetitive protein, which does not become functional until the noncoding RNA transcript undergoes multiple rounds of reverse transcription by the linked DRT2 enzyme [16, 17]. Antisense promoter is reconstituted only after reverse transcription; however, it is still unknown how cDNA synthesis is triggered by phage infection. Other defense-associated RTs are still awaiting elucidation of the mechanisms conferring resistance to viral infection. Another case of promoter combinatorics is exemplified by integrons, bacterial systems that rearrange gene cassettes to aid adaptability under stress. Promoter-containing toxin-antitoxin cassettes play a key role in controlling cassette excision rates from arrays, to maintain genome integrity and facilitate integron maintenance and diversification [18].

Structural studies of TE-encoded protein/nucleic acid complexes

This year, landmark papers solved high-resolution 3-D structures of the most intensively studied human retrotransposon, L1 (LINE-1) [19, 20]. Further, TE structural biologists also reported on TEs capable of site-specific integration, such as R2 retrotransposons inserting into the rDNA target, with insect R2Bm structure solved last year [21, 22]. The rDNA target is believed to represent a ‘safe harbor’ for transgene insertion, and with that in mind, cryo-EM structures of vertebrate R2 proteins, avian and testudine, were used to uncover the basis for nucleic acid recognition, and to capture the RNP conformation after the second-strand nicking [23]. The bacterial transposon Tn7 also receives a lot of attention from structural biologists due to its ability for programmable RNA-guided transposition [24, 25]. These studies underscore the importance of RNA in defining the specificity of interaction with the target and the potential for its reprogramming.

Applications in biomedicine and biotechnology

Our increased understanding of TE biology has already yielded tangible advances in novel strategies for genome engineering based on RNA-guided DNA integration and target-primed reverse transcription [26,27,28,29]. Several biotech companies are advancing these technologies towards the clinic, and the interest in exploiting the potential of TEs to reshape genomes continues to grow. Also of note is the technique of retron-mediated ‘recombineering’, which allows multiplexed editing of a single phage genome without counterselection, using modified retrons (“recombitrons”) [30]. Harnessing TE expression for innate immune signaling [31] or to produce immunostimulatory antigens [32] in contexts of cancer treatment are also areas of active investigation.

Concluding remarks

Whether controlling or controlled, TEs interact extensively with their hosts, promoting evolutionary dynamics and generating variability via TE-host evolutionary arms races, TE co-options and domestications, regulatory changes, and the restructuring of genomic compartments. Mobile DNA is now inviting submissions to several collections on popular topics suggested by new editorial board members, which encompass TEs in epigenetic control, endogenous viral elements, horizontal transfer, cancer and aging, and cis-regulation of gene expression (https://biomedcentral-mobilednajournal.publicaciones.saludcastillayleon.es). The pervasive influence of TEs on nearly every major developing area of modern biology, combined with immense potential for further discoveries, makes this highly dynamic field equally attractive to researchers immersed in it for a long time or recently drawn to it from other fields. We look forward to what new knowledge 2025 will bring.