The human silencing hub (HUSH) complex is a transcription-dependent, epigenetic repressor complex that provides a genome-wide immunosurveillance system for the recognition and silencing of newly-integrated retroelements. The core HUSH complex of TASOR, MPP8 and Periphilin, represses these retroelements through SETDB1-mediated H3K9me3 deposition and MORC2-dependent chromatin compaction. HUSH-dependent silencing is RNA-mediated, yet no HUSH component contains a recognised RNA-binding domain. Here we used an unbiased approach to identify which HUSH component was able to bind RNA and determine whether RNA-binding was essential for HUSH function. We identify Periphilin as the major RNA-binding component of the HUSH complex and show that Periphilin's N-terminal domain is essential for both RNA binding and HUSH function. Periphilin binding to RNA was independent of its interaction with TASOR or MPP8, as its N-terminal domain was sufficient for RNA targeting. The artificial tethering of Periphilin to a HUSH-insensitive, nascent transcript, enabled the HUSH-dependent silencing of the transcript. This tethering of Periphilin allowed the RNA-binding region of Periphilin to be removed such that only its C-terminal domain was required for oligomerisation and interaction with TASOR. We therefore show that Periphilin is the predominant RNA-binding protein of the HUSH complex and this RNA-binding is essential for HUSH activity.

中文翻译：

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Periphilin 的 RNA 结合在 HUSH 复合物启动沉默中起着重要作用


人类沉默枢纽 （HUSH） 复合物是一种转录依赖性的表观遗传阻遏蛋白复合物，可提供全基因组免疫监测系统，用于识别和沉默新整合的逆转录元件。TASOR、MPP8 和 Periphilin 的核心 HUSH 复合物通过 SETDB1 介导的 H3K9me3 沉积和 MORC2 依赖性染色质压缩抑制这些逆转录元件。HUSH 依赖性沉默是 RNA 介导的，但没有 HUSH 组分包含公认的 RNA 结合结构域。在这里，我们使用了一种无偏倚的方法来确定哪个 HUSH 组分能够结合 RNA，并确定 RNA 结合是否对 HUSH 功能至关重要。我们确定 Periphilin 是 HUSH 复合物的主要 RNA 结合组分，并表明 Periphilin 的 N 末端结构域对 RNA 结合和 HUSH 功能都是必不可少的。Periphilin 与 RNA 的结合与它与 TASOR 或 MPP8 的相互作用无关，因为它的 N 末端结构域足以进行 RNA 靶向。Periphilin 与 HUSH 不敏感的新生转录本的人工拴系，使转录本的 HUSH 依赖性沉默成为可能。Periphilin 的这种栓系允许去除 Periphilin 的 RNA 结合区域，因此只需要其 C 端结构域进行寡聚化和与 TASOR 的相互作用。因此，我们表明 Periphilin 是 HUSH 复合物的主要 RNA 结合蛋白，这种 RNA 结合对于 HUSH 活性至关重要。