小柯机器人

英国剑桥大学Paul J. Lehner团队发现，HUSH通过介导无内含子移动元件的沉默来监控基因组。相关论文于2021年11月18日在线发表在《自然》杂志上。

据研究人员介绍，所有的生命形式都在保卫它们的基因组免受DNA入侵。真核细胞识别进入的DNA并通过抑制性染色质修饰限制转录。人类沉默枢纽（HUSH）复合体通过组蛋白H3 Lys9三甲基化（H3K9me3）转录抑制长穿插元件-1逆转座子（L1s）和逆转录病毒。HUSH如何识别并启动对这些入侵遗传元件的沉默是未知的。

研究人员发现，HUSH能够识别和转录抑制广泛的长的、无内含子的转基因。即使在没有内含子剪接的情况下，内含子插入到HUSH抑制的转基因中也能抵消抑制。HUSH在H3K9me3沉积之前和不依赖于H3K9me3沉积的情况下，与来自目标基因座的转录本结合，目标转录对HUSH介导的H3K9me3启动和扩散都是必不可少的。基因组数据揭示了HUSH是如何结合并抑制通过细胞mRNA的逆转座产生的内源性无内含子基因亚群。因此，无内含子的cDNA是逆转录的标志，它提供了一种通用的手段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"非己"DNA的影响，尽管之前没有接触过侵元件。

这些研究结果揭示了一个依赖于转录的基因组监控系统，并解释了它是如何对新获得的元件提供即时保护，同时避免对宿主基因进行不适当的抑制。

附：英文原文

Title: Genome surveillance by HUSH-mediated silencing of intronless mobile elements

Author: Seczynska, Marta, Bloor, Stuart, Cuesta, Sergio Martinez, Lehner, Paul J.

Issue&Volume: 2021-11-18

Abstract: All life forms defend their genome against DNA invasion. Eukaryotic cells recognize incoming DNA and limit transcription through repressive chromatin modifications. The human silencing hub (HUSH) complex transcriptionally represses long interspersed element-1 retrotransposons (L1s) and retroviruses through histone H3 Lys9 trimethylation (H3K9me3)1–3. 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. Therefore, intronless cDNA, the hallmark of reverse transcription, provides a versatile means to distinguish invading retroelements from host genes and allows HUSH to protect the genome from ‘non-self’ DNA, despite no prior 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.

DOI: 10.1038/s41586-021-04228-1

Source: https://www.nature.com/articles/s41586-021-04228-1

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