Abstract
LINE-1 (L1) retrotransposons are repetitive elements in mammalian genomes. They are capable of synthesizing DNA on their own RNA templates by harnessing reverse transcriptase (RT) that they encode. Abundantly expressed full-length L1s and their RT are found to globally influence gene expression profiles, differentiation state, and proliferation capacity of early embryos and many types of cancer, albeit by yet unknown mechanisms. They are essential for the progression of early development and the establishment of a cancer-related undifferentiated state. This raises important questions regarding the functional significance of L1 RT in these cell systems. Massive nuclear L1-linked reverse transcription has been shown to occur in mouse zygotes and two-cell embryos, and this phenomenon is purported to be DNA replication independent. This review argues against this claim with the goal of understanding the nature of this phenomenon and the role of L1 RT in early embryos and cancers. Available L1 data are revisited and integrated with relevant findings accumulated in the fields of replication timing, chromatin organization, and epigenetics, bringing together evidence that strongly supports two new concepts. First, noncanonical replication of a portion of genomic full-length L1s by means of L1 RNP-driven reverse transcription is proposed to co-exist with DNA polymerase-dependent replication of the rest of the genome during the same round of DNA replication in embryonic and cancer cell systems. Second, the role of this mechanism is thought to be epigenetic; it might promote transcriptional competence of neighboring genes linked to undifferentiated states through the prevention of tethering of involved L1s to the nuclear periphery. From the standpoint of these concepts, several hitherto inexplicable phenomena can be explained. Testing methods for the model are proposed.ReviewersThis article was reviewed by Dr. Philip Zegerman (nominated by Dr. Orly Alter), Dr. I. King Jordan, and Dr. Panayiotis (Takis) Benos. For the complete reviews, see the Reviewers’ Reports section.
Highlights
L1 elements have propagated in mammalian genomes by means of autonomous retrotransposition
A novel concept is required to explain the nature of massive L1-linked reverse transcription at the onset of embryogenesis and how abundantly expressed full-length L1 (FL-L1) RNA and reverse transcriptase (RT) can globally control the epigenetic state of a cell
A revised L1 paradigm should put into focus the possibility of L1 RT-driven biologically significant processes other than retrotransposition
Summary
L1 elements have propagated in mammalian genomes by means of autonomous retrotransposition. A study of replication timing and transcription profiles of a variety of independent cell lines representing different stages of early mouse embryogenesis [46] has revealed that (i) loss of pluripotency is associated with a number of EtoL replication-timing changes, which are lineage-independent and completed by the late postimplantation epiblast stage prior to germ layer specification and are stably maintained in all downstream lineages; (ii) these EtoL changes precede the downregulation of key pluripotency transcription factors [POU5F1 ( known as OCT4)/NANOG/SOX2]; (iii) these EtoL replicationtiming changes tend to be accompanied by a repositioning of these domains toward the nuclear periphery and a downregulation of genes residing in these segments, especially those with low CpG density promoters; (iv) the completion of lineage-independent EtoL changes coincides with a transition of these EtoL domains to a stable silent epigenetic state, which is very difficult to reprogram back to the pluripotent state in terms of replication timing and the expression of genes with low CpG density promoters; (v) DNA methylation of genes with low CpG density promoters within these EtoL domains and activity of several chromatin modifying enzymes are not a main cause of the established irreversibility; (vi) the acquired stable silencing of lineage-independent EtoL domains on autosomes is reminiscent of the irreversible heterochromatinization of the inactive X chromosome (Xi) in female mammals and occurs within the same time frame in development; (vii) the subnuclear repositioning of EtoL domains occurs in parallel with a dramatic switch to chromatin compaction along the nuclear envelope; and (viii) these lineageindependent EtoL domains represent 6.1% or 155 Mb of the genome. More detail on the sequences of the FL-L1 RNAs forming the full-size L1 RNPs in cancers would open a new avenue in the field of cancer biomarkers
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