L1 retrotransposition in neurons is modulated by MeCP2.
L1 retrotransposition in neurons is modulated by MeCP2.
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长散布核元件-1（LINE-1或L1）是一种丰富的反转录转座子，约占哺乳动物基因组的20%。活跃的L1反转录转座子可以以多种方式影响基因组，产生插入、缺失、新的剪接位点或基因表达微调。我们之前已经证明L1逆转录转座子能够在啮齿动物和人类的神经元祖细胞中动员，并且在成人脑组织中观察到大量L1插入的证据，但在其他体组织中没有观察到。此外，L1在成年海马的流动性可以受到环境的影响。体细胞L1逆转录转座在神经祖细胞中的神经元特异性部分是由于Sox 2/HDAC 1阻遏物复合物转变为Wnt介导的T细胞因子/淋巴增强因子（TCF/LEF）转录激活因子。在神经元分化过程中，转录开关伴随着染色质重塑，允许L1转录的瞬时刺激。L1反转录转座子在大脑发育过程中的活性可以对基因表达和神经元功能产生影响，从而增加大脑特异性遗传镶嵌。进一步了解调节L1表达的分子机制，将为L1逆转录转座在脑发育过程中的作用提供新的见解。在这里，我们表明，L1神经元的转录和反转录转座在啮齿动物中的甲基-CpG结合蛋白2（MeCP 2），参与全球DNA甲基化和人类神经发育疾病的蛋白质的情况下增加。使用来自人类诱导多能干细胞和人类组织的神经元祖细胞，我们发现携带MeCP 2突变的Rett综合征（RTT）患者对L1逆转录的易感性增加。我们的数据表明，L1反转录可以控制在一个组织特异性的方式和疾病相关的基因突变可以影响神经元L1反转录的频率。我们的发现为可能导致神经系统疾病的分子事件增加了新的复杂性。
Long interspersed nuclear elements-1 (LINE-1 or L1s) are abundant retrotransposons that comprise approximately 20% of mammalian genomes,,. Active L1 retrotransposons can impact the genome in a variety of ways, creating insertions, deletions, new splice sites or gene expression fine-tuning,,. We have shown previously that L1 retrotransposons are capable of mobilization in neuronal progenitor cells from rodents and humans and evidence of massive L1 insertions was observed in adult brain tissues but not in other somatic tissues,. In addition, L1 mobility in the adult hippocampus can be influenced by the environment. The neuronal specificity of somatic L1 retrotransposition in neural progenitors is partially due to the transition of a Sox2/HDAC1 repressor complex to a Wnt-mediated T-cell factor/lymphoid enhancer factor (TCF/LEF) transcriptional activator,. The transcriptional switch accompanies chromatin remodelling during neuronal differentiation, allowing a transient stimulation of L1 transcription. The activity of L1 retrotransposons during brain development can have an impact on gene expression and neuronal function, thereby increasing brain-specific genetic mosaicism,. Further understanding of the molecular mechanisms that regulate L1 expression should provide new insights into the role of L1 retrotransposition during brain development. Here we show that L1 neuronal transcription and retrotransposition in rodents are increased in the absence of methyl-CpG-binding protein 2 (MeCP2), a protein involved in global DNA methylation and human neurodevelopmental diseases. Using neuronal progenitor cells derived from human induced pluripotent stem cells and human tissues, we revealed that patients with Rett syndrome (RTT), carrying MeCP2 mutations, have increased susceptibility for L1 retrotransposition. Our data demonstrate that L1 retrotransposition can be controlled in a tissue-specific manner and that disease-related genetic mutations can influence the frequency of neuronal L1 retrotransposition. Our findings add a new level of complexity to the molecular events that can lead to neurological disorders.
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