L1 retrotransposition in human neural progenitor cells

Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Nature (Impact Factor: 41.46). 09/2009; 460(7259):1127-31. DOI: 10.1038/nature08248
Source: PubMed


Long interspersed element 1 (LINE-1 or L1) retrotransposons have markedly affected the human genome. L1s must retrotranspose in the germ line or during early development to ensure their evolutionary success, yet the extent to which this process affects somatic cells is poorly understood. We previously demonstrated that engineered human L1s can retrotranspose in adult rat hippocampus progenitor cells in vitro and in the mouse brain in vivo. Here we demonstrate that neural progenitor cells isolated from human fetal brain and derived from human embryonic stem cells support the retrotransposition of engineered human L1s in vitro. Furthermore, we developed a quantitative multiplex polymerase chain reaction that detected an increase in the copy number of endogenous L1s in the hippocampus, and in several regions of adult human brains, when compared to the copy number of endogenous L1s in heart or liver genomic DNAs from the same donor. These data suggest that de novo L1 retrotransposition events may occur in the human brain and, in principle, have the potential to contribute to individual somatic mosaicism.

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Available from: Nicole G Coufal, Sep 30, 2015
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    • "Previously, evidence for L1 insertions in normal somatic cells has come from two sources. A number of studies have shown that somatic L1 insertions occur in neuronal development and are present in various sites in the human and mouse brain (Muotri et al. 2005; Coufal et al. 2009; Baillie et al. 2011; Evrony et al. 2012; Upton et al. 2015). Moreover, a small number of examples of L1, SVA, and processed pseudogene insertions have been reported to occur in early human development (van den Hurk et al. 2007; de Boer et al. 2014; Vogt et al. 2014). "
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    ABSTRACT: Somatic L1 retrotransposition events have been shown to occur in epithelial cancers. Here, we attempted to determine how early somatic L1 insertions occurred during the development of gastrointestinal (GI) cancers. Using L1-targeted resequencing (L1-seq), we studied different stages of four colorectal cancers arising from colonic polyps, seven pancreatic carcinomas, as well as seven gastric cancers. Surprisingly, we found somatic L1 insertions not only in all cancer types and metastases, but also in colonic adenomas, well-known cancer precursors. Some insertions were also present in low quantities in normal GI tissues, occasionally caught in the act of being clonally fixed in the adjacent tumors. Insertions in adenomas and cancers numbered in the hundreds and many were present in multiple tumor sections implying clonal distribution. Our results demonstrate that extensive somatic insertional mutagenesis occurs very early during the development of GI tumors, probably before dysplastic growth. Published by Cold Spring Harbor Laboratory Press.
    Genome Research 08/2015; DOI:10.1101/gr.196238.115 · 14.63 Impact Factor
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    • "The genomic load of endogenous L1-ORF2 and IAPΔ1 elements was within normal values in 4N (meiotic ), 2N (non-meiotic), and even apoptotic Dnmt3L −/− cells. This is in striking contrast to formerly described situations of TE reactivation in which de novo integration events were readily detectable using similar methods (Coufal et al. 2009; Ciaudo et al. 2013). Although we cannot exclude that a few TEs may mobilize, these data collectively argue that the genome of Dnmt3L −/− spermatocytes does not undergo massive retrotransposition. "
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    ABSTRACT: DNA methylation is essential for protecting the mammalian germline against transposons. When DNA methylation-based transposon control is defective, meiotic chromosome pairing is consistently impaired during spermatogenesis: How and why meiosis is vulnerable to transposon activity is unknown. Using two DNA methylation-deficient backgrounds, the Dnmt3L and Miwi2 mutant mice, we reveal that DNA methylation is largely dispensable for silencing transposons before meiosis onset. After this, it becomes crucial to back up to a developmentally programmed H3K9me2 loss. Massive retrotransposition does not occur following transposon derepression, but the meiotic chromatin landscape is profoundly affected. Indeed, H3K4me3 marks gained over transcriptionally active transposons correlate with formation of SPO11-dependent double-strand breaks and recruitment of the DMC1 repair enzyme in Dnmt3L(-/-) meiotic cells, whereas these features are normally exclusive to meiotic recombination hot spots. Here, we demonstrate that DNA methylation restrains transposons from adopting chromatin characteristics amenable to meiotic recombination, which we propose prevents the occurrence of erratic chromosomal events. © 2015 Zamudio et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & development 06/2015; 29(12). DOI:10.1101/gad.257840.114 · 10.80 Impact Factor
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    • "There is also evidence that retroelements and transposons are highly active during brain development and in neural progenitor cells (NPCs) (Muotri et al., 2005, 2010; Baillie et al., 2011; Evrony et al., 2012; Li et al., 2013; Perrat et al., 2013). For example, LINE-1 elements have been found to be transcriptionally active and to retrotranspose in NPCs (Muotri et al., 2005, 2010; Coufal et al., 2009). In addition, we have previously found that deletion of TRIM28 in postmitotic forebrain neurons results in complex behavioral alterations, including vulnerability to stress (Jakobsson et al., 2008). "
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    ABSTRACT: TRIM28 is a corepressor that mediates transcriptional silencing by establishing local heterochromatin. Here, we show that deletion of TRIM28 in neural progenitor cells (NPCs) results in high-level expression of two groups of endogenous retroviruses (ERVs): IAP1 and MMERVK10C. We find that NPCs use TRIM28-mediated histone modifications to dynamically regulate transcription and silencing of ERVs, which is in contrast to other somatic cell types using DNA methylation. We also show that derepression of ERVs influences transcriptional dynamics in NPCs through the activation of nearby genes and the expression of long noncoding RNAs. These findings demonstrate a unique dynamic transcriptional regulation of ERVs in NPCs. Our results warrant future studies on the role of ERVs in the healthy and diseased brain. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 12/2014; 10(1). DOI:10.1016/j.celrep.2014.12.004 · 8.36 Impact Factor
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