Engineered LINE-1 retrotransposition in nondividing human neurons.
Engineered LINE-1 retrotransposition in nondividing human neurons.
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DOI：
10.1101/gr.206805.116
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发表时间：
2017-03
期刊：
影响因子：
7
通讯作者：
Garcia-Perez JL
中科院分区：
文献类型：
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作者：
Macia A;Widmann TJ;Heras SR;Ayllon V;Sanchez L;Benkaddour-Boumzaouad M;Muñoz-Lopez M;Rubio A;Amador-Cubero S;Blanco-Jimenez E;Garcia-Castro J;Menendez P;Ng P;Muotri AR;Goodier JL;Garcia-Perez JL
人类基因组的一半是由转座因子（TE）组成的，其持续的活动继续影响着我们的基因组。LINE-1（或L1）是人类基因组中的自主非LTR反转录转座子，占其基因组质量的17%，并且每个平均基因组含有平均80-100个活性L1，其提供个体间变异的来源。新的LINE-1插入被认为主要在人类胚胎发生期间积累。令人惊讶的是，L1 s的活性可以进一步影响人体大脑基因组。然而，目前尚不清楚L1是否可以在其他躯体健康组织中逆转录转座，或者L1动员是否仅限于人脑中的神经元前体细胞（NPC）。在这里，我们利用了一个工程L1逆转录转座试验，以分析L1动员率在人类间充质（MSC）和造血（HSC）体干细胞。值得注意的是，我们已经观察到，与NPC相比，MSC和HSC中的L1表达和工程化逆转录转座要低得多。值得注意的是，我们首次进一步证明了工程L1可以在成熟的非分裂神经元细胞中有效地逆转录转座。因此，这些发现表明，体细胞镶嵌的程度和L1反转录在人脑中的影响可能比以前认为的要高得多。
Half the human genome is made of transposable elements (TEs), whose ongoing activity continues to impact our genome. LINE-1 (or L1) is an autonomous non-LTR retrotransposon in the human genome, comprising 17% of its genomic mass and containing an average of 80–100 active L1s per average genome that provide a source of inter-individual variation. New LINE-1 insertions are thought to accumulate mostly during human embryogenesis. Surprisingly, the activity of L1s can further impact the somatic human brain genome. However, it is currently unknown whether L1 can retrotranspose in other somatic healthy tissues or if L1 mobilization is restricted to neuronal precursor cells (NPCs) in the human brain. Here, we took advantage of an engineered L1 retrotransposition assay to analyze L1 mobilization rates in human mesenchymal (MSCs) and hematopoietic (HSCs) somatic stem cells. Notably, we have observed that L1 expression and engineered retrotransposition is much lower in both MSCs and HSCs when compared to NPCs. Remarkably, we have further demonstrated for the first time that engineered L1s can retrotranspose efficiently in mature nondividing neuronal cells. Thus, these findings suggest that the degree of somatic mosaicism and the impact of L1 retrotransposition in the human brain is likely much higher than previously thought.