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. 2010 Aug;33(8):345-54.
doi: 10.1016/j.tins.2010.04.001. Epub 2010 May 12.

LINE-1 retrotransposons: mediators of somatic variation in neuronal genomes?

Tatjana Singer  1 , Michael J McConnell, Maria C N Marchetto, Nicole G Coufal, Fred H Gage
Affiliations

LINE-1 retrotransposons: mediators of somatic variation in neuronal genomes?

Tatjana Singer et al. Trends Neurosci. 2010 Aug.

Abstract

LINE-1 (L1) elements are retrotransposons that insert extra copies of themselves throughout the genome using a 'copy and paste' mechanism. L1s comprise nearly approximately 20% of the human genome and are able to influence chromosome integrity and gene expression upon reinsertion. Recent studies show that L1 elements are active and 'jumping' during neuronal differentiation. New somatic L1 insertions could generate 'genomic plasticity' in neurons by causing variation in genomic DNA sequences and by altering the transcriptome of individual cells. Thus, L1-induced variation could affect neuronal plasticity and behavior. We discuss potential consequences of L1-induced neuronal diversity and propose that a mechanism for generating diversity in the brain could broaden the spectrum of behavioral phenotypes that can originate from any single genome.

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Conflict of interest statement

DISCLOSURE STATEMENT

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Background on L1 retrotransposition
A| Composition of L1 and dependent sequences. L1 elements belong to the long interspersed element (LINEs) class of repeat sequences and are the only active class of retroelements in the human genome. Full-length, functional L1s are ~6kb long and are autonomous because they encode proteins necessary for their retrotransposition. L1 elements contain a polymerase II promoter in their 5′UTR (blue band, with arrow), followed by two open reading frames (ORF1 and ORF2) and a short 3′-UTR that ends in a poly(A) tail. The poly(A) tail is preceded by a polyadenylation signal (pA). ORF1 encodes a nucleic acid chaperone [75]; ORF2 encodes an endonuclease and reverse transcriptase [76]. Both of the element-encoded proteins are essential for retrotransposition. Another class of repeats in mammalian genomes are short interspersed elements (SINEs). SINEs are sequences that do not encode for their own proteins necessary for transposition but can be mobilized by L1- encoded proteins and are therefore non-autonomous. SINEs that can be transactivated by L1 are Alu and SVA elements. SVA elements are ~3kb long, do not contain a transcriptional promoter sequence and consist of several components (SINE-R, VNTR, Alu), including a hexanucleotide repeat sequence at their 5′ end (CCCTCTn) and a poly(A) tail at their 3′ end; (VNTR, variable number of tandem repeats). Alu elements are short ~300bp long sequences that contain two polymerase III promoter regions (blue bands, with arrows) and consist of two related monomers: left monomer (LM) and right monomer (RM). Both monomers are separated by an A-rich linker region (An). Alu elements usually end in a long poly(A) tract. A hallmark of all novel L1-mediated retrotransposon insertions is that they are flanked by target site duplications (TSDs, black arrows) of varying lengths. Processed pseudogenes are generated from spliced mRNAs that have hijacked the L1 machinery, were reverse transcribed, and inserted into the genome. They consist of intron-less exonic sequences and typically do not include a promoter sequence. If inserted near a regulatory region they can become expressed and exert regulatory functions [77, 78]. B| L1 retrotransposition cycle. L1 transcription is repressed by methylation (Me) of the CpG island in its promoter. Once transcribed, L1 mRNA (blue line) is exported from the nucleus and translated in the cytoplasm, where it assembles with its own encoded proteins, which show a strong cis-preference and forms ribonucleoprotein complexes (RNPs). RNP complexes are re-imported into the nucleus, probably due to nuclear envelope breakdown during mitosis. L1 RNA is reinserted in the genome by a proposed mechanism referred to as target site primed reverse transcription (TPRT), whereby the endonuclease makes a single-stranded nick in the host DNA (consensus sequence: 5′-TTTT/AA-3′) [27] and the reverse transcriptase uses the nicked DNA to prime reverse transcription from the 3′ end of the L1 RNA. Frequently, reverse transcription fails to proceed to the 5′ end, resulting in truncated de novo insertions that are unable to jump again. L1 mRNA and proteins can be sequestered into stress granules (SGs) [79]. SGs are discrete cytoplasmic aggregates that are induced by a range of stress conditions, including hypoxia, heat shock and oxidative stress. Two possible functions of SGs in the context of L1 biogenesis have been discussed: L1-RNPs could be either targeted for degradation or return from SGs to the polysome-associated cytoplasmic pool of translated mRNAs [80], which upon re-entry into the nucleus would lead to new L1 insertions in the genomic DNA. In addition to L1, Alus, SVAs or cellular mRNAs can be “hijacked” by L1 proteins, thus facilitating their retrotransposition into the genome and possibly generating additional variation. C| L1 regulation during neurogenesis. L1 transcription is repressed in neural stem cells (NSCs) by a complex comprised of the transcription factor SOX2 and histone deacetylase 1 (HDAC1). SOX2 binds to a bipartite sequence motif that also contains a LEF binding site. Derepression of the SOX2/HDAC1 complex occurs during the transition from NSCs to neural progenitor cells (NPCs); subsequently L1 expression is induced by Wnt signaling: WNT3A activates β–catenin, which then accumulates in the nucleus where it forms an activating complex with TCF/LEF. The TCF/LEF complex can now bind to the LEF binding site that has been vacated by SOX2 leading to the transcriptional activation (bent black arrow) and jumping (curved red arrows) of L1 elements.
Figure 2
Figure 2. How L1 insertion may affect the transcriptome
A| In a process termed transduction, L1 elements (golden cylinders) carry sequences flanking the element from their original source location to a new location; this can occur on the 5′ and 3′ end: transcription that initiates upstream from the L1 element results in mRNA that contains additional sequence 5′ of the L1 element (red line), whereas poly-adenylation sites that are located further downstream of the L1 element can lead to extension of L1 mRNA beyond the element’s 3′ end (green line). This process can cause exon shuffling or lead to insertion of regulatory sequences such as transcription factor binding sites at a new genomic location. B| Mammalian L1 elements (golden cylinders) contain functional splice sites in both sense and antisense (AS) orientations; thus, when integrated into introns, L1 elements can induce aberrant splicing resulting in alternative mRNA transcripts. C| L1 elements contain numerous internal polyadenylation [(p(A)] signals in both sense and antisense orientation that can lead to alternative mRNA transcripts or premature termination, thus affecting mRNA splicing and stability. D| Transcript levels of genes can be changed through regulatory sequences that are contained within L1 elements. Human L1 elements contain one sense and one antisense promoter within their 5′ UTR and another promoter in the 3′ UTR (bent arrows). The antisense promoter in the 5′ and 3′ UTRs can initiate ectopic transcription of sequences flanking L1. Antisense transcripts can lead to production of non-coding RNA (ncRNA) or chimeric transcripts. Further, antisense RNA could reduce mRNA levels through the formation of double-stranded RNA (dsRNA), triggering the protein kinase R (PKR) degradation pathway [81], or leading to siRNA that induces RISC-dependent silencing [82]. In addition, ncRNAs could modulate epigenetic marks in cis and aid in the establishment of boundary elements. E| An L1 element that has inserted upstream of another gene can become methylated (Me), which may induce formation of heterochromatin (red ovals) that can spread into flanking promoter sequences, effectively silencing transcription. Conversely, activation of an inserted L1 element could lead to ectopic activation of a nearby gene by facilitating binding of transcription factors (green oval).
Figure 3
Figure 3. Putative implications of L1-mediated somatic mosaicism in the brain
In a reversal of the commonly held belief that retrotransposition occurs primarily in the germline [83], it became clear that L1 elements are expressed in many somatic tissues, including the brain [7, 13, 84]. Recent evidence shows that L1 retrotransposition (curved red arrows) does not occur in the parental germline but in the soma during early embryonic development (colored dots), resulting in individuals that are genetically mosaic with respect to L1 composition [33]. It has been suggested, however, that L1 RNA may be transcribed in the parental germline and carried over in both male and female germ cells in the form of RNPs (black line with red dots) and integrated into the genome at the preimplantation stage [33] (colored spots); however, these events are probably rare, since retrotransposons are effectively silenced in the germline through a small RNA induced mechanism [78, 85]. Somatic L1 retrotranspositon events that occur during embryogenesis would result in clonal sectors of cells (colored patches) that carry the same insertion event. The size of clonal sectors depends on the developmental stage when the insertion occurred and the number of subsequent cell divisions. L1 insertion events that happen during embryonic brain development will be found in different brain regions (colored patches and dots), whereas events that happen during adult neurogenesis will be restricted to specific areas, such as the dentate gyrus (insert). According to our hypothesis, L1-induced mosaicism could increase variability in the brain (blue curve), which could have implications for behavioral phenotypes. The environment could influence regulation of somatic L1 retrotransposition in the brain and this influence could be mediated by epigenetic or hormonal mechanisms. Depending on its impact on the brain and the consequences, L1-induced somatic variability could either increase the risk for neurological disease or induce behavioral changes that could help the organism to better adapt to changing environments.
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