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: 42.35). 09/2009; 460(7259):1127-31. DOI: 10.1038/nature08248
Source: PubMed

ABSTRACT 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, Aug 19, 2015
    • "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 insertion 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 · 13.85 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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    • "In E. cyanostictus brain, each sex overexpressed a different class of transposable elements: A polinton DNA transposon in females and a gypsy retrotransposon in males. Active transposable elements in the brain have been associated with aging and neuronal decline (Coufal et al. 2009; Li et al. 2013). "
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    ABSTRACT: Males and females of the same species differ largely in gene expression, which accounts for most of the morphological and physiological differences and sex-specific phenotypes. Here, we analyzed sex-specific gene expression in the brain and the gonads of cichlid fishes from Lake Tanganyika belonging to four different lineages, so-called tribes (Eretmodini, Ectodini, Haplochromini and Lamprologini), using the outgroup Nile tilapia (Oreochromis niloticus) as reference. The comparison between male and female brain revealed few differences between the sexes, consistent in all investigated species. The gonads, on the other hand, showed a large fraction of differentially expressed transcripts with the majority of them showing the same direction of expression in all four species. All here-studied cichlids, especially the three investigated mouth-breeding species, showed a trend towards more male- than female-biased transcripts. Transcripts, which were female-biased in expression in all four species, were overrepresented on LG1 in the reference genome and common male-biased transcripts showed accumulation on LG23, the presumable sex chromosomes of the Nile tilapia. Sex-specific transcripts contained candidate genes for sex determination and differentiation in fishes, especially members of the TGF-β-superfamily and the Wnt-pathway and also prominent members of the sox-, dm-domain- and HMG-box families. We further confirmed our previous finding on species/lineage-specific gene expression shifts in the sex steroid pathway including synthesizing enzymes as the aromatase cyp19a1 and estrogen and androgen receptors.
    Genome Biology and Evolution 09/2014; DOI:10.1093/gbe/evu200 · 4.53 Impact Factor
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