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Transposable elements (TEs) such as endogenous retroviruses (ERVs), long interspersed nuclear elements (LINEs), and short interspersed nuclear elements (SINEs) occupy nearly half of typical mammalian genomes. Previous studies show that these parasitic elements, especially LINEs and ERVs, provide important activities promoting host germ cell and placental development, preimplantation embryogenesis, and maintenance of pluripotent stem cells. Despite being the most numerically abundant type of TEs in the genome, the consequences of SINEs on host genome regulation are less well characterized than those of ERVs and LINEs. Interestingly, recent findings reveal that SINEs recruit the key architectural protein CTCF (CCCTC-binding factor), indicating a role of these elements for 3D genome regulation. Higher-order nuclear structures are linked with important cellular functions such as gene regulation and DNA replication. SINEs and other TEs, therefore, may mediate distinct physiological processes with benefits to the host by modulating the 3D genome.

Section snippetsRole of transposable elements in mammalian development

Transposable elements (TEs), as their name suggests, can move around the host genome. Retrotransposons using copy-(transcription)-and-paste (reverse transcription/integration) mechanisms predominate and are the only known actively mobile TEs in human and mouse genomes. TE insertion events are thought to be mostly neutral or deleterious for the host, and therefore these sequences have been traditionally regarded as junk DNA. The importance of limiting the mutagenesis of TE insertion events is

Transposable elements may mediate responses to various environmental cues

TEs are attractive candidates to mediate environmentally responsive or adaptive transgenerational epigenetic inheritance, owing to their function as metastable epialleles 12, 13. Metastable epialleles, made famous by the discovery of the Agouti viable yellow (AVY) allele in mice [14], have been defined as “alleles that are variably expressed in genetically identical individuals due to epigenetic modifications established during early development” [13]. In the AVY allele, an intracisternal

Short interspersed nuclear elements and their functions in transcriptional regulation

Short interspersed nuclear element (SINE) (and its human example Alu) sequences are the most abundant TEs in mammals in terms of copy number, possessing more than one million copies and occupying about 10% of the mouse or human genome. In comparison to LINEs and ERVs, full-length copies of which are several kilobases long, SINEs are much smaller with a length of several hundred bases. Furthermore, LINEs and ERVs are autonomous TEs that can retrotranspose by their own, but SINEs are entirely

Short interspersed nuclear elements and long interspersed nuclear elements as mediators of higher-order genome organization

An important, yet perhaps less-explored, role of TEs involves higher-order genome regulation. The mammalian genome contains about three billion base pairs of DNA molecules that are packaged neatly within the nucleus having a diameter of only 10 μM. This impressive degree of compression is achieved in part by segregating the genome into densely packed and gene-poor heterochromatin, and relatively open and gene-rich euchromatin. It has been noted that SINEs are enriched in euchromatin, while

CTCF binding to short interspersed nuclear elements might be associated with phenotypic diversity

Most of the CTCF-binding sites in humans or mice are species-specific [35], indicating that the gain of SINEs in a species may have contributed to CTCF binding and in turn higher-order genome folding in that species. Such functional divergence SINEs for recruitment of CTCF may not be restricted to species level and might also operate among different strains of the same species, and even among different individuals within a population. This view has been supported by a recent study that analyzed

Roles of transposable elements as sources of novel regulatory elements in the host genome

TEs, due to being multicopy elements and polymorphic, are a major force for creating and disseminating new regulatory sequences such as enhancers and anchoring motifs for chromatin loops in the host genome (Figure 1). Expanding this notion further, a recent study reported that specific families and subfamilies of TEs contribute to 3D interactions in the genome in both lineage- and species-specific manners [43]. The lineage-specific nature of TE-derived regulatory sequences has been highlighted

Potential roles of short interspersed nuclear element and long interspersed nuclear element RNAs in liquid–liquid-phase separation?

Biophysical phenomena such as droplet formation and liquid–liquid-phase separation (LLPS) play important roles for higher-order genome folding by promoting homophilic interactions between euchromatin and euchromatin, or heterochromatin and heterochromatin. LLPS is mediated by proteins that can undergo phase separation. Interestingly, CTCF can form phase-separated clusters within the nucleus, and promotes transcriptional condensates containing RNAP2, bromodomain-containing 2 (BRD2), or mediator

Functional roles of short interspersed nuclear element and long interspersed nuclear element RNAs

SINE elements possess internal motifs that can facilitate CTCF binding, and thereby provide mobile CTCF-binding sites within the host genome. Given the affinity of CTCF for SINE sequences, it is tempting to hypothesize that SINE RNA may also play a role to recruit CTCF. The molecular roles of SINE RNA, however, are poorly understood. One reason behind this is the difficulty to detect SINE RNA in biological samples. Like mRNAs, ERV- or LINE-derived RNAs are also transcribed by RNAP2 and are

Concluding remarks

As discussed above, recent studies indicate that TEs may facilitate higher-order genome regulation via homotypic interactions between elements of the same family. Some TEs, such as SINEs, also appear to be highly suited for recruitment of specific architectural proteins such as CTCF. As a result, divergence of TE sequences between species, or polymorphism of TEs within a population, could have created functional plasticity via modulating the higher-order genome (Figure 1). Such functions, in

Editorial disclosure statement

Given the role as Guest Editor, Haruhiko Koseki had no involvement in the peer review of the article and has no access to information regarding its peer-review. Full responsibility for the editorial process of this article was delegated to Joseph Reese.

Conflict of interest statement

The authors declare no conflict of interest.

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