Long interspersed nuclear element-1 (LINE-1 or L1) is a retrotransposon group that constitutes 17% of the human genome and shows variable expression across cell types. However, the control of L1 expression and its function in gene regulation are incompletely understood. Here we show that L1 transcription activates long-range gene expression. Genome-wide CRISPR–Cas9 screening using a reporter driven by the L1 5′ UTR in human cells identifies functionally diverse genes affecting L1 expression. Unexpectedly, altering L1 expression by knockout of regulatory genes impacts distant gene expression. L1s can physically contact their distal target genes, with these interactions becoming stronger upon L1 activation and weaker when L1 is silenced. Remarkably, L1s contact and activate genes essential for zygotic genome activation (ZGA), and L1 knockdown impairs ZGA, leading to developmental arrest in mouse embryos. These results characterize the regulation and function of L1 in long-range gene activation and reveal its importance in mammalian ZGA.

长散布核元件 1（LINE-1 或 L1）是一种反转录转座子群，占人类基因组的 17%，并在不同细胞类型中表现出不同的表达。然而，L1 表达的控制及其在基因调控中的功能尚不完全清楚。在这里，我们证明 L1 转录激活长程基因表达。使用由人类细胞中的 L1 5' UTR 驱动的报告基因进行全基因组 CRISPR-Cas9 筛选，识别影响 L1 表达的功能多样的基因。出乎意料的是，通过敲除调控基因来改变 L1 表达会影响远处基因的表达。 L1 可以物理接触它们的远端靶基因，这些相互作用在 L1 激活时变得更强，而在 L1 沉默时变得更弱。值得注意的是，L1 接触并激活合子基因组激活 (ZGA) 所必需的基因，而 L1 敲低会损害 ZGA，导致小鼠胚胎发育停滞。这些结果表征了 L1 在长程基因激活中的调节和功能，并揭示了其在哺乳动物 ZGA 中的重要性。