Department of Genetics, University of Cambridge, Cambridge CB2 3EH, United Kingdom.
Departamento de Biomedicina, Unidade de Biologia Experimental, Faculdade de Medicina da Universidade do Porto, Porto; and i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-319 Porto, Portugal.
Genome Res. 2018 Mar 1;28(3):345-356. doi: 10.1101/gr.221366.117.
Approximately half the mammalian genome is composed of repetitive sequences, and accumulating evidence suggests that some may have an impact on genome function. Here, we characterized a large array class of repeats of long-interspersed elements (LINE-1). Although widely distributed in mammals, locations of such arrays are species specific. Using targeted deletion, we asked whether a 170-kb LINE-1 array located at a mouse imprinted domain might function as a modulator of local transcriptional control. The LINE-1 array is lamina associated in differentiated ES cells consistent with its AT-richness, and although imprinting occurs both proximally and distally to the array, active LINE-1 transcripts within the tract are biallelically expressed. Upon deletion of the array, no perturbation of imprinting was observed, and abnormal phenotypes were not detected in maternal or paternal heterozygous or homozygous mutant mice. The array does not shield nonimprinted genes in the vicinity from local imprinting control. Reduced neural expression of protein-coding genes observed upon paternal transmission of the deletion is likely due to the removal of a brain-specific enhancer embedded within the LINE array. Our findings suggest that presence of a 170-kb LINE-1 array reflects the tolerance of the site for repeat insertion rather than an important genomic function in normal development.
大约一半的哺乳动物基因组由重复序列组成，越来越多的证据表明，其中一些可能对基因组功能有影响。在这里，我们对长散布元件（LINE-1）的一类大型重复阵列进行了特征描述。尽管这些阵列广泛分布于哺乳动物中，但它们的位置具有物种特异性。通过靶向删除，我们询问位于小鼠印记区域的 170kb LINE-1 阵列是否可能作为局部转录控制的调节剂发挥作用。LINE-1 阵列在分化的 ES 细胞中与核纤层相关，这与其富含 AT 有关，尽管印记发生在阵列的近端和远端，但该区域内的活性 LINE-1 转录物是双等位基因表达的。在删除该阵列后，没有观察到印记的扰动，并且在母系或父系杂合或纯合突变小鼠中也没有检测到异常表型。该阵列不会屏蔽附近非印记基因的局部印记控制。在父系遗传缺失时观察到的编码蛋白基因的神经表达减少可能是由于嵌入 LINE 阵列中的大脑特异性增强子被去除。我们的研究结果表明，170kb LINE-1 阵列的存在反映了该位点对重复插入的容忍性，而不是正常发育中重要的基因组功能。
