All life forms defend their genome against DNA invasion. Eukaryotic cells recognize incoming DNA and limit its transcription through repressive chromatin modifications. The human silencing hub (HUSH) complex transcriptionally represses long interspersed element-1 retrotransposons (L1s) and retroviruses through histone H3 lysine 9 trimethylation (H3K9me3)^1,2,3. How HUSH recognizes and initiates silencing of these invading genetic elements is unknown. Here we show that HUSH is able to recognize and transcriptionally repress a broad range of long, intronless transgenes. Intron insertion into HUSH-repressed transgenes counteracts repression, even in the absence of intron splicing. HUSH binds transcripts from the target locus, prior to and independent of H3K9me3 deposition, and target transcription is essential for both initiation and propagation of HUSH-mediated H3K9me3. Genomic data reveal how HUSH binds and represses a subset of endogenous intronless genes generated through retrotransposition of cellular mRNAs. Thus intronless cDNA—the hallmark of reverse transcription—provides a versatile way to distinguish invading retroelements from host genes and enables HUSH to protect the genome from ‘non-self’ DNA, despite there being no previous exposure to the invading element. Our findings reveal the existence of a transcription-dependent genome-surveillance system and explain how it provides immediate protection against newly acquired elements while avoiding inappropriate repression of host genes.

所有生命形式都保护其基因组免受 DNA 入侵。真核细胞识别传入的 DNA 并通过抑制性染色质修饰限制其转录。人类沉默中枢 (HUSH) 复合体通过组蛋白 H3 赖氨酸 9 三甲基化 (H3K9me3) ^{1,2,3转录抑制长散布 element-1 逆转录转座子 (L1s) 和逆转录病毒}. HUSH 如何识别并启动这些入侵遗传元素的沉默尚不清楚。在这里，我们表明 HUSH 能够识别和转录抑制范围广泛的无内含子的长转基因。内含子插入到 HUSH 抑制的转基因中会抵消抑制，即使在没有内含子剪接的情况下也是如此。HUSH 在 H3K9me3 沉积之前并独立于目标基因座结合转录物，目标转录对于 HUSH 介导的 H3K9me3 的启动和传播都是必不可少的。基因组数据揭示了 HUSH 如何结合和抑制通过细胞 mRNA 逆转录转座产生的内源性无内含子基因的子集。因此，无内含子的 cDNA（逆转录的标志）提供了一种通用的方法来区分入侵的逆转录元件和宿主基因，并使 HUSH 能够保护基因组免受“非自身”DNA 的影响，尽管之前没有接触过入侵元件。我们的发现揭示了依赖转录的基因组监测系统的存在，并解释了它如何针对新获得的元素提供即时保护，同时避免对宿主基因的不当抑制。