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Biochemical Society Transactions Nov 2021Plant genomes are largely comprised of retrotransposons which can replicate through 'copy and paste' mechanisms. Long terminal repeat (LTR) retrotransposons are the... (Review)
Review
Plant genomes are largely comprised of retrotransposons which can replicate through 'copy and paste' mechanisms. Long terminal repeat (LTR) retrotransposons are the major class of retrotransposons in plant species, and importantly they broadly affect the expression of nearby genes. Although most LTR retrotransposons are non-functional, active retrotranspositions have been reported in plant species or mutants under normal growth condition and environmental stresses. With the well-defined reference genome and numerous mutant alleles, Arabidopsis studies have significantly expanded our understanding of retrotransposon regulation. Active LTR retrotransposon loci produce virus-like particles to perform reverse transcription, and their complementary DNA can be inserted into new genomic loci. Due to the detrimental consequences of retrotransposition, plants like animals, have developed transcriptional and post-transcriptional silencing mechanisms. Recently several different genome-wide techniques have been developed to understand LTR retrotransposition in Arabidopsis and different plant species. Transposome, methylome, transcriptome, translatome and small RNA sequencing data have revealed how host silencing mechanisms can affect multiple steps of retrotransposition. These recent advances shed light on future mechanistic studies of retrotransposition as well as retrotransposon diversity.
Topics: Arabidopsis; DNA Replication; Epigenesis, Genetic; Gene Expression Regulation, Plant; Gene Silencing; Genes, Plant; Retroelements; Transcriptional Activation
PubMed: 34495315
DOI: 10.1042/BST20210337 -
Nature May 2023Throughout an individual's lifetime, genomic alterations accumulate in somatic cells. However, the mutational landscape induced by retrotransposition of long...
Throughout an individual's lifetime, genomic alterations accumulate in somatic cells. However, the mutational landscape induced by retrotransposition of long interspersed nuclear element-1 (L1), a widespread mobile element in the human genome, is poorly understood in normal cells. Here we explored the whole-genome sequences of 899 single-cell clones established from three different cell types collected from 28 individuals. We identified 1,708 somatic L1 retrotransposition events that were enriched in colorectal epithelium and showed a positive relationship with age. Fingerprinting of source elements showed 34 retrotransposition-competent L1s. Multidimensional analysis demonstrated that (1) somatic L1 retrotranspositions occur from early embryogenesis at a substantial rate, (2) epigenetic on/off of a source element is preferentially determined in the early organogenesis stage, (3) retrotransposition-competent L1s with a lower population allele frequency have higher retrotransposition activity and (4) only a small fraction of L1 transcripts in the cytoplasm are finally retrotransposed in somatic cells. Analysis of matched cancers further suggested that somatic L1 retrotransposition rate is substantially increased during colorectal tumourigenesis. In summary, this study illustrates L1 retrotransposition-induced somatic mosaicism in normal cells and provides insights into the genomic and epigenomic regulation of transposable elements over the human lifetime.
Topics: Humans; Carcinogenesis; Colorectal Neoplasms; DNA Transposable Elements; Genomics; Long Interspersed Nucleotide Elements; Retroelements; Aging; Gene Frequency; Mosaicism; Epigenomics; Genome, Human; Colon; Intestinal Mucosa; Embryonic Development
PubMed: 37165195
DOI: 10.1038/s41586-023-06046-z -
Genes & Development Dec 2023Long interspersed element 1 (LINE-1) is the only protein-coding transposon that is active in humans. LINE-1 propagates in the genome using RNA intermediates via... (Review)
Review
Long interspersed element 1 (LINE-1) is the only protein-coding transposon that is active in humans. LINE-1 propagates in the genome using RNA intermediates via retrotransposition. This activity has resulted in LINE-1 sequences occupying approximately one-fifth of our genome. Although most copies of LINE-1 are immobile, ∼100 copies are retrotransposition-competent. Retrotransposition is normally limited via epigenetic silencing, DNA repair, and other host defense mechanisms. In contrast, LINE-1 overexpression and retrotransposition are hallmarks of cancers. Here, we review mechanisms of LINE-1 regulation and how LINE-1 may promote genetic heterogeneity in tumors. Finally, we discuss therapeutic strategies to exploit LINE-1 biology in cancers.
Topics: Humans; Long Interspersed Nucleotide Elements; Neoplasms; RNA; Proteins; Epigenesis, Genetic
PubMed: 38092519
DOI: 10.1101/gad.351051.123 -
IScience Oct 2023Long interspersed element 1 (LINE-1) is the only currently known active autonomous transposon in humans, and its retrotransposition may cause deleterious effects on the...
Long interspersed element 1 (LINE-1) is the only currently known active autonomous transposon in humans, and its retrotransposition may cause deleterious effects on the structure and function of host cell genomes and result in sporadic genetic diseases. Host cells therefore developed defense strategies to restrict LINE-1 mobilization. In this study, we demonstrated that IFN-inducible Schlafen5 (SLFN5) inhibits LINE-1 retrotransposition. Mechanistic studies revealed that SLFN5 interrupts LINE-1 ribonucleoprotein particle (RNP) formation, thus diminishing nuclear entry of the LINE-1 RNA template and subsequent LINE-1 cDNA production. The ability of SLFN5 to bind to LINE-1 RNA and the involvement of the helicase domain of SLFN5 in its inhibitory activity suggest a mechanism that SLFN5 binds to LINE-1 RNA followed by dissociation of ORF1p through its helicase activity, resulting in impaired RNP formation. These data highlight a new mechanism of host cells to restrict LINE-1 mobilization.
PubMed: 37810251
DOI: 10.1016/j.isci.2023.107968 -
Briefings in Functional Genomics Jul 2010Studies of large imprinted clusters, such as the Gnas locus, have revealed much about the significance of DNA methylation, transcription and other factors in the... (Review)
Review
Studies of large imprinted clusters, such as the Gnas locus, have revealed much about the significance of DNA methylation, transcription and other factors in the establishment and maintenance of imprinted gene expression. However, the complexity of such loci can make manipulating them and interpreting the results challenging. We review here a distinct class of imprinted genes, which have arisen by retrotransposition, and which have the potential to be used as models for the dissection of the fundamental features and mechanisms required for imprinting. They are also of interest in their own right, generating diversity in the transcriptome and providing raw material upon which selection can act.
Topics: Animals; DNA Methylation; Epigenesis, Genetic; Genomic Imprinting; Humans; Models, Genetic; Retroelements
PubMed: 20591835
DOI: 10.1093/bfgp/elq015 -
Mobile DNA 2018Retrotransposons are transposable elements (TEs) capable of "jumping" in germ, embryonic and tumor cells and, as is now clearly established, in the neuronal lineage.... (Review)
Review
Retrotransposons are transposable elements (TEs) capable of "jumping" in germ, embryonic and tumor cells and, as is now clearly established, in the neuronal lineage. Mosaic TE insertions form part of a broader landscape of somatic genome variation and hold significant potential to generate phenotypic diversity, in the brain and elsewhere. At present, the LINE-1 (L1) retrotransposon family appears to be the most active autonomous TE in most mammals, based on experimental data obtained from disease-causing L1 mutations, engineered L1 reporter systems tested in cultured cells and transgenic rodents, and single-cell genomic analyses. However, the biological consequences of almost all somatic L1 insertions identified thus far remain unknown. In this review, we briefly summarize the current state-of-the-art in the field, including estimates of L1 retrotransposition rate in neurons. We bring forward the hypothesis that an extensive subset of retrotransposition-competent L1s may be de-repressed and mobile in the soma but largely inactive in the germline. We discuss recent reports of non-canonical L1-associated sequence variants in the brain and propose that the elevated L1 DNA content reported in several neurological disorders may predominantly comprise accumulated, unintegrated L1 nucleic acids, rather than somatic L1 insertions. Finally, we consider the main objectives and obstacles going forward in elucidating the biological impact of somatic retrotransposition.
PubMed: 30002735
DOI: 10.1186/s13100-018-0128-1 -
ELife Apr 2023LINE-1 (L1) is the only autonomously active retrotransposon in the human genome, and accounts for 17% of the human genome. The L1 mRNA encodes two proteins, ORF1p and...
LINE-1 (L1) is the only autonomously active retrotransposon in the human genome, and accounts for 17% of the human genome. The L1 mRNA encodes two proteins, ORF1p and ORF2p, both essential for retrotransposition. ORF2p has reverse transcriptase and endonuclease activities, while ORF1p is a homotrimeric RNA-binding protein with poorly understood function. Here, we show that condensation of ORF1p is critical for L1 retrotransposition. Using a combination of biochemical reconstitution and live-cell imaging, we demonstrate that electrostatic interactions and trimer conformational dynamics together tune the properties of ORF1p assemblies to allow for efficient L1 ribonucleoprotein (RNP) complex formation in cells. Furthermore, we relate the dynamics of ORF1p assembly and RNP condensate material properties to the ability to complete the entire retrotransposon life-cycle. Mutations that prevented ORF1p condensation led to loss of retrotransposition activity, while orthogonal restoration of coiled-coil conformational flexibility rescued both condensation and retrotransposition. Based on these observations, we propose that dynamic ORF1p oligomerization on L1 RNA drives the formation of an L1 RNP condensate that is essential for retrotransposition.
Topics: Humans; Retroelements; Long Interspersed Nucleotide Elements; Mutation; RNA-Binding Proteins; RNA
PubMed: 37114770
DOI: 10.7554/eLife.82991 -
Chromosome Research : An International... Mar 2018Long interspersed element-1 (LINE-1 or L1) retrotransposons represent the only functional family of autonomous transposable elements in humans and formed 17% of our... (Review)
Review
Long interspersed element-1 (LINE-1 or L1) retrotransposons represent the only functional family of autonomous transposable elements in humans and formed 17% of our genome. Even though most of the human L1 sequences are inactive, a limited number of copies per individual retain the ability to mobilize by a process termed retrotransposition. The ongoing L1 retrotransposition may result in insertional mutagenesis that could lead to negative consequences such as genetic disease and cancer. For this reason, cells have evolved several mechanisms of defense to restrict L1 activity. Among them, a critical role for cellular deaminases [activation-induced deaminase (AID)/apolipoprotein B mRNA-editing catalytic polypeptide-like (APOBEC) and adenosine deaminases that act on RNA (ADAR) enzymes] has emerged. The majority of the AID/APOBEC family of proteins are responsible for the deamination of cytosine to uracil (C-to-U editing) within DNA and RNA targets. The ADARs convert adenosine bases to inosines (A-to-I editing) within double-stranded RNA (dsRNA) targets. This review will discuss the current understanding of the regulation of LINE-1 retrotransposition mediated by these enzymes.
Topics: APOBEC Deaminases; Adenosine Deaminase; Cytidine Deaminase; DNA; Humans; Long Interspersed Nucleotide Elements; RNA; RNA, Double-Stranded; Retroelements
PubMed: 29396793
DOI: 10.1007/s10577-018-9572-5 -
Virus Genes 1995One of the more interesting developments in herpesvirus evolution concerns the acquisition of novel, non-ubiquitous herpesvirus genes. A number of these are related to... (Review)
Review
One of the more interesting developments in herpesvirus evolution concerns the acquisition of novel, non-ubiquitous herpesvirus genes. A number of these are related to known cellular genes. How did herpesviruses acquire such genes? Our recent demonstration of retrovirus integration into herpesviruses suggests a potentially important role for retrotransposition in herpesvirus evolution and in the acquisition of novel genes, cellular in origin. Herpesvirus genome development has been characterized by a number of structural and evolutionary properties that support this proposal. We first discuss the evidence for retroviral integration into herpesviruses. The functional significance of this phenomenon is presently unclear. However, in the broader context of retrotransposition, a number of attractive features serve to explain the capture of structural and regulatory elements throughout herpesvirus evolution. These possibilities are discussed in detail.
Topics: Animals; Evolution, Molecular; Gene Transfer Techniques; Herpesviridae; Humans; RNA, Viral; Recombination, Genetic; Retroelements; Retroviridae
PubMed: 8828151
DOI: 10.1007/BF01728664 -
Viruses May 2017The human LINE-1 (or L1) element is a non-LTR retrotransposon that is mobilized through an RNA intermediate by an L1-encoded reverse transcriptase and other L1-encoded... (Review)
Review
The human LINE-1 (or L1) element is a non-LTR retrotransposon that is mobilized through an RNA intermediate by an L1-encoded reverse transcriptase and other L1-encoded proteins. L1 elements remain actively mobile today and continue to mutagenize human genomes. Importantly, when new insertions disrupt gene function, they can cause diseases. Historically, L1s were thought to be active in the germline but silenced in adult somatic tissues. However, recent studies now show that L1 is active in at least some somatic tissues, including epithelial cancers. In this review, we provide an overview of these recent developments, and examine evidence that somatic L1 retrotransposition can initiate and drive tumorigenesis in humans. Recent studies have: (i) cataloged somatic L1 activity in many epithelial tumor types; (ii) identified specific full-length L1 source elements that give rise to somatic L1 insertions; and (iii) determined that L1 promoter hypomethylation likely plays an early role in the derepression of L1s in somatic tissues. A central challenge moving forward is to determine the extent to which L1 driver mutations can promote tumor initiation, evolution, and metastasis in humans.
Topics: Carcinogenesis; Humans; Long Interspersed Nucleotide Elements; Neoplasms; Recombination, Genetic; Retroelements
PubMed: 28561751
DOI: 10.3390/v9060131