组蛋白伴侣 FACT 抑制逆转录转座子 MERVL 和 MERVL 衍生的隐匿启动子。
Histone chaperone FACT represses retrotransposon MERVL and MERVL-derived cryptic promoters.
机构信息
State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300350, People's Republic of China.
College of Pharmacy, Nankai University, Tianjin 300350, People's Republic of China.
出版信息
Nucleic Acids Res. 2020 Oct 9;48(18):10211-10225. doi: 10.1093/nar/gkaa732.
Endogenous retroviruses (ERVs) were usually silenced by various histone modifications on histone H3 variants and respective histone chaperones in embryonic stem cells (ESCs). However, it is still unknown whether chaperones of other histones could repress ERVs. Here, we show that H2A/H2B histone chaperone FACT plays a critical role in silencing ERVs and ERV-derived cryptic promoters in ESCs. Loss of FACT component Ssrp1 activated MERVL whereas the re-introduction of Ssrp1 rescued the phenotype. Additionally, Ssrp1 interacted with MERVL and suppressed cryptic transcription of MERVL-fused genes. Remarkably, Ssrp1 interacted with and recruited H2B deubiquitinase Usp7 to Ssrp1 target genes. Suppression of Usp7 caused similar phenotypes as loss of Ssrp1. Furthermore, Usp7 acted by deubiquitinating H2Bub and thereby repressed the expression of MERVL-fused genes. Taken together, our study uncovers a unique mechanism by which FACT complex silences ERVs and ERV-derived cryptic promoters in ESCs.
内源性逆转录病毒（ERVs）通常在胚胎干细胞（ESCs）中通过各种组蛋白修饰和相应的组蛋白伴侣沉默。然而，其他组蛋白的伴侣是否能抑制ERVs 仍然未知。在这里，我们发现 H2A/H2B 组蛋白伴侣 FACT 在沉默 ESCs 中的 ERVs 和 ERV 衍生的隐匿启动子时发挥关键作用。FACT 成分 Ssrp1 的缺失激活了 MERVL，而 Ssrp1 的重新引入挽救了表型。此外，Ssrp1 与 MERVL 相互作用并抑制 MERVL 融合基因的隐匿转录。值得注意的是，Ssrp1 相互作用并募集 H2B 去泛素化酶 Usp7 到 Ssrp1 靶基因。Usp7 的抑制导致与 Ssrp1 缺失相似的表型。此外，Usp7 通过去泛素化 H2Bub 从而抑制 MERVL 融合基因的表达。总之，我们的研究揭示了 FACT 复合物在 ESCs 中沉默 ERVs 和 ERV 衍生的隐匿启动子的独特机制。
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