Epigenetic silencing of engineered L1 retrotransposition events in human embryonic carcinoma cells. Nature

Department of Human Genetics, 1241 East Catherine Street, University of Michigan Medical School, Ann Arbor, Michigan 48109-5618, USA.
Nature (Impact Factor: 41.46). 08/2010; 466(7307):769-73. DOI: 10.1038/nature09209
Source: PubMed

ABSTRACT Long interspersed element-1 (LINE-1 or L1) retrotransposition continues to affect human genome evolution. L1s can retrotranspose in the germline, during early development and in select somatic cells; however, the host response to L1 retrotransposition remains largely unexplored. Here we show that reporter genes introduced into the genome of various human embryonic carcinoma-derived cell lines (ECs) by L1 retrotransposition are rapidly and efficiently silenced either during or immediately after their integration. Treating ECs with histone deacetylase inhibitors rapidly reverses this silencing, and chromatin immunoprecipitation experiments revealed that reactivation of the reporter gene was correlated with changes in chromatin status at the L1 integration site. Under our assay conditions, rapid silencing was also observed when reporter genes were delivered into ECs by mouse L1s and a zebrafish LINE-2 element, but not when similar reporter genes were delivered into ECs by Moloney murine leukaemia virus or human immunodeficiency virus, suggesting that these integration events are silenced by distinct mechanisms. Finally, we demonstrate that subjecting ECs to culture conditions that promote differentiation attenuates the silencing of reporter genes delivered by L1 retrotransposition, but that differentiation, in itself, is not sufficient to reactivate previously silenced reporter genes. Thus, our data indicate that ECs differ from many differentiated cells in their ability to silence reporter genes delivered by L1 retrotransposition.

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    • "Notably, additional studies have demonstrated that TE methylation differs between cell types, these epigenetic modifications being related to global gene regulation patterns [83] [84] [85]. On the other hand, an active epigenetic response to new L1 insertions in pluripotent cells seem to be related to controlling the load of germline mobilization throughout evolution ([86], reviewed in [57] [78]). Additionally, in adult somatic stem cells such as neural stem cells (NSCs), Methyl-CpG-binding protein 2 (MeCP2), a protein involved in global DNA methylation and human neurodevelopmental diseases, along with transcriptional factors such as Sox2 and the histone deacetylase 1 protein (HDAC1), form a repressor complex on the L1 promoter region controlling L1 neuronal transcription and thus retrotransposition [87] [88] [89]. "
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    • "CpG sites [Cordaux et al., 2006]. The many host silencing mechanisms , although largely unexplored, appear to be particularly complex [Bogerd et al., 2006; Tanay et al., 2007; Aravin and Bourc'his, 2008; Edwards et al., 2010; Garcia-Perez et al., 2010; McCue and Slotkin, 2012; Schmidt et al., 2012; Ahn et al., 2013; Horn et al., 2013; Ward et al., 2013]. Despite the sophisticated machinery used by the cell to regulate TE activity, some TEs escape repression and generate new insertions in germ cells during early embryonic development, as well as, in somatic tissues later in life [Baillie et al., 2011; Kazazian, 2011; Lee et al., 2012]. "
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    • "We speculate that the determinants of variable initiation of RIFTs by various L1s across the genome may include position effects, neighboring transcription units, other nearby genomic features, tissue-specific factors and/or variable chromatin marks (16). Alternatively, certain L1 integrants could undergo differential, transcriptional gene silencing in situ (72) (Kannan,M. et al., in preparation). "
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