Department of Human Genetics, 1241 East Catherine Street, University of Michigan Medical School, Ann Arbor, Michigan 48109-5618, USA.
Nature. 2010 Aug 5;466(7307):769-73. doi: 10.1038/nature09209.
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.
长散布元件 1（LINE-1 或 L1）逆转录转座持续影响人类基因组进化。L1 可以在生殖细胞、早期发育和某些体细胞中转录；然而，宿主对 L1 逆转录转座的反应在很大程度上仍未被探索。在这里，我们表明，通过 L1 逆转录转座引入各种人胚胎癌细胞系（ECs）基因组中的报告基因，在整合过程中或之后很快被有效地沉默。用组蛋白去乙酰化酶抑制剂处理 ECs 可迅速逆转这种沉默，染色质免疫沉淀实验表明，报告基因的重新激活与 L1 整合位点染色质状态的变化相关。在我们的测定条件下，当报告基因通过小鼠 L1 和斑马鱼 LINE-2 元件被递送至 ECs 时，也观察到快速沉默，但当类似的报告基因被递送至 ECs 时通过莫洛尼鼠白血病病毒或人类免疫缺陷病毒，表明这些整合事件受到不同机制的沉默。最后，我们证明，使 ECs 处于促进分化的培养条件下会减弱由 L1 逆转录转座递送至报告基因的沉默，但分化本身不足以重新激活先前沉默的报告基因。因此，我们的数据表明，与许多分化细胞相比，ECs 能够沉默由 L1 逆转录转座递送至报告基因。
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